rs786205642
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001849.4(COL6A2):c.1997G>A(p.Ser666Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S666R) has been classified as Uncertain significance.
Frequency
Consequence
NM_001849.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A2 | NM_001849.4 | c.1997G>A | p.Ser666Asn | missense_variant | 26/28 | ENST00000300527.9 | |
COL6A2 | NM_058174.3 | c.1997G>A | p.Ser666Asn | missense_variant | 26/28 | ENST00000397763.6 | |
COL6A2 | NM_058175.3 | c.1997G>A | p.Ser666Asn | missense_variant | 26/28 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A2 | ENST00000300527.9 | c.1997G>A | p.Ser666Asn | missense_variant | 26/28 | 1 | NM_001849.4 | P1 | |
COL6A2 | ENST00000397763.6 | c.1997G>A | p.Ser666Asn | missense_variant | 26/28 | 5 | NM_058174.3 | ||
COL6A2 | ENST00000409416.6 | c.1997G>A | p.Ser666Asn | missense_variant | 25/27 | 5 | |||
COL6A2 | ENST00000413758.1 | c.668G>A | p.Ser223Asn | missense_variant | 11/11 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 23, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre | - | - - |
Bethlem myopathy 1A Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | This missense change has been observed in individual(s) with Bethlem myopathy (PMID: 18378883, 25211533). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 666 of the COL6A2 protein (p.Ser666Asn). ClinVar contains an entry for this variant (Variation ID: 191318). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at