rs1555873523
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_001849.4(COL6A2):c.1078G>T(p.Ala360Ser) variant causes a missense change. 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. A360G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
COL6A2
NM_001849.4 missense
NM_001849.4 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 4.71
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 4 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 6 uncertain in NM_001849.4
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1078G>T | p.Ala360Ser | missense_variant | 12/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1078G>T | p.Ala360Ser | missense_variant | 12/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1078G>T | p.Ala360Ser | missense_variant | 12/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1078G>T | p.Ala360Ser | missense_variant | 12/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1078G>T | p.Ala360Ser | missense_variant | 12/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1078G>T | p.Ala360Ser | missense_variant | 11/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 15, 2017 | This sequence change replaces alanine with serine at codon 360 of the COL6A2 protein (p.Ala360Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL6A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N;N;N
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
D;P;P;D
Vest4
MutPred
Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);
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