rs886044088
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_001849.4(COL6A2):c.848G>A(p.Gly283Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
COL6A2
NM_001849.4 missense
NM_001849.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 6.30
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001849.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr21-46115917-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 871767.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
?
Variant 21-46115918-G-A is Pathogenic according to our data. Variant chr21-46115918-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46115918-G-A is described in Lovd as [Pathogenic]. Variant chr21-46115918-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.848G>A | p.Gly283Glu | missense_variant | 6/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.848G>A | p.Gly283Glu | missense_variant | 6/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.848G>A | p.Gly283Glu | missense_variant | 6/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.848G>A | p.Gly283Glu | missense_variant | 6/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.848G>A | p.Gly283Glu | missense_variant | 6/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.848G>A | p.Gly283Glu | missense_variant | 5/27 | 5 | |||
COL6A2 | ENST00000485591.1 | n.504G>A | non_coding_transcript_exon_variant | 2/7 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 26, 2019 | This variant replaces the Glycine position in the GXY motif within the triple helical region of the COL6A2 protein; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29277723, 24038877) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 26, 2016 | - - |
Bethlem myopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 24, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly283 amino acid residue in COL6A2. Other variant(s) that disrupt this residue have been observed in individuals with COL6A2-related conditions (PMID: 15689448, 24038877), which suggests that this may be a clinically significant amino acid residue. 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: 289114). This missense change has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 24038877). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 283 of the COL6A2 protein (p.Gly283Glu). - |
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
Uncertain
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
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;D
Vest4
MutPred
Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at