21-46132385-C-A
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_001849.4(COL6A2):c.2893C>A(p.Arg965Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R965H) has been classified as Likely benign.
Frequency
Consequence
NM_001849.4 missense
Scores
Clinical Significance
Conservation
Publications
- collagen 6-related myopathyInheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
- Ullrich congenital muscular dystrophy 1BInheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
- Bethlem myopathy 1AInheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
- Ullrich congenital muscular dystrophy 1AInheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- Bethlem myopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Ullrich congenital muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- myosclerosisInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.2893C>A | p.Arg965Ser | missense_variant | Exon 28 of 28 | ENST00000300527.9 | NP_001840.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt COL6A2 protein function. This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 965 of the COL6A2 protein (p.Arg965Ser). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at