rs886042705

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001849.4(COL6A2):c.901G>A(p.Gly301Ser) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G301D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL6A2
NM_001849.4 missense, splice_region

Scores

Splicing: ADA: 0.2268

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.11

Variant links:

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]

COL6A2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-46116378-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 21-46116377-G-A is Pathogenic according to our data. Variant chr21-46116377-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 283758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46116377-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-46116377-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 8 of 28	ENST00000300527.9	NP_001840.3	P12110-1A0A384MDP3
COL6A2	NM_058174.3 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 8 of 28		NP_478054.2	P12110-2
COL6A2	NM_058175.3 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 8 of 28		NP_478055.2	P12110-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL6A2	ENST00000300527.9 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 8 of 28	1	NM_001849.4	ENSP00000300527.4	P12110-1
COL6A2	ENST00000397763.6 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 8 of 28	5		ENSP00000380870.1	P12110-2
COL6A2	ENST00000409416.6 link	c.901G>A	p.Gly301Ser	missense_variant, splice_region_variant	Exon 7 of 27	5		ENSP00000387115.1	P12110-3
COL6A2	ENST00000485591.1 link	n.557G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 1A

Pathogenic:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 301 of the COL6A2 protein (p.Gly301Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant COL6A2-related conditions (PMID: 24271325, 30564623). ClinVar contains an entry for this variant (Variation ID: 283758). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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). This variant disrupts the p.Gly301 amino acid residue in COL6A2. Other variant(s) that disrupt this residue have been observed in individuals with COL6A2-related conditions (PMID: 17785673, 24271325), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;H;H;H

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0050

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.94

MutPred

0.93

Gain of phosphorylation at G301 (P = 0.0124);Gain of phosphorylation at G301 (P = 0.0124);Gain of phosphorylation at G301 (P = 0.0124);Gain of phosphorylation at G301 (P = 0.0124);

MVP

0.98

MPC

0.57

ClinPred

1.0

GERP RS

4.1

Varity_R

0.74

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.23

dbscSNV1_RF

Benign

0.33

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over