rs116099212

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

The FREM2 p.Val2968Ile variant was not identified in Cosmic but was identified in dbSNP (ID: rs116099212), ClinVar (classified as benign by EGL Genetic Diagnostics and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 1149 of 282828 chromosomes (6 homozygous) at a frequency of 0.004063 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 811 of 129136 chromosomes (freq: 0.00628), South Asian in 154 of 30616 chromosomes (freq: 0.00503), Other in 28 of 7226 chromosomes (freq: 0.003875), European (Finnish) in 67 of 25122 chromosomes (freq: 0.002667), Latino in 61 of 35438 chromosomes (freq: 0.001721), African in 24 of 24974 chromosomes (freq: 0.000961), Ashkenazi Jewish in 3 of 10364 chromosomes (freq: 0.00029), and East Asian in 1 of 19952 chromosomes (freq: 0.00005). This variant was identified in the heterozygous state in one case with a prenatal diagnosis of laryngeal atresia/stenosis although the clinical significance of this variant is not known (Drury_2015_PMID:26275891). The p.Val2968 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26275891)