rs1555873827
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001849.4(COL6A2):c.1199G>T(p.Gly400Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G400R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1199G>T | p.Gly400Val | missense_variant | 14/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1199G>T | p.Gly400Val | missense_variant | 14/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1199G>T | p.Gly400Val | missense_variant | 14/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1199G>T | p.Gly400Val | missense_variant | 14/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1199G>T | p.Gly400Val | missense_variant | 14/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1199G>T | p.Gly400Val | missense_variant | 13/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1459872Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726304
GnomAD4 genome ? Cov.: 34
ClinVar
Submissions by phenotype
Bethlem myopathy 1A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2017 | In summary, this variant is a novel missense change affecting a residue that is critical for protein structure, stability and function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with COL6A2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 400 of the COL6A2 protein (p.Gly400Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. 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 disease (PMID: 15689448, 24038877) compared to the general population (ExAC). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at