rs774521989
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5
The NM_001849.4(COL6A2):c.2633C>T(p.Ala878Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000076 in 1,579,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A878A) has been classified as Likely benign.
Frequency
Consequence
NM_001849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.2633C>T | p.Ala878Val | missense_variant | 28/28 | ENST00000300527.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.2633C>T | p.Ala878Val | missense_variant | 28/28 | 1 | NM_001849.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000161 AC: 3AN: 186134Hom.: 0 AF XY: 0.00000983 AC XY: 1AN XY: 101760
GnomAD4 exome AF: 0.00000350 AC: 5AN: 1427532Hom.: 0 Cov.: 33 AF XY: 0.00000424 AC XY: 3AN XY: 708070
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152216Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 08, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 26, 2016 | - - |
Bethlem myopathy 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 878 of the COL6A2 protein (p.Ala878Val). This variant is present in population databases (rs774521989, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of autosomal recessive COL6A2-related conditions (PMID: 33481221; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 210748). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL6A2 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 07, 2015 | - - |
Ullrich congenital muscular dystrophy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 04, 2022 | The homozygous p.Ala878Val variant in COL6A2 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. The variant has not been previously reported in individuals with Ullrich congenital muscular dystrophy 1 but has been identified in 0.01% (2/19182) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs774521989). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 210748) as likely pathogenic by Genetic Services Laboratory, University of Chicago, and as uncertain significance by Invitae and EGL Genetic Diagnostics, Eurofins Clinical Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3_supporting (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at