rs765430501
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_001849.4(COL6A2):c.1288G>A(p.Gly430Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,563,986 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).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
COL6A2
NM_001849.4 missense
NM_001849.4 missense
Scores
14
4
1
Clinical Significance
Conservation
PhyloP100: 6.20
Genes affected
COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.804
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1288G>A | p.Gly430Ser | missense_variant | 15/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1288G>A | p.Gly430Ser | missense_variant | 15/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1288G>A | p.Gly430Ser | missense_variant | 15/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1288G>A | p.Gly430Ser | missense_variant | 15/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1288G>A | p.Gly430Ser | missense_variant | 15/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1288G>A | p.Gly430Ser | missense_variant | 14/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152036Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000229 AC: 4AN: 174532Hom.: 0 AF XY: 0.0000324 AC XY: 3AN XY: 92558
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GnomAD4 exome AF: 0.0000156 AC: 22AN: 1411950Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 12AN XY: 697422
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 18, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 13, 2015 | The G430S variant in the COL6A2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G430S variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G430S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G430S variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded. - |
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 10, 2023 | 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. This variant disrupts the triple helix domain of COL6A2. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A2, missense variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). 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. ClinVar contains an entry for this variant (Variation ID: 289769). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 430 of the COL6A2 protein (p.Gly430Ser). - |
COL6A2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 17, 2023 | The COL6A2 c.1288G>A variant is predicted to result in the amino acid substitution p.Gly430Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0051% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/21-47539720-G-A). This variant affects a Gly residue of the conserved triple helical domain, where substitutions of the glycine are frequently pathogenic (Butterfield et al. 2013. PubMed ID: 24038877). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);Gain of phosphorylation at G430 (P = 0.0022);
MVP
MPC
ClinPred
D
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at