rs727502828

Positions:

• chr21-46116027-G-A
• chr21-46116027-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001849.4(COL6A2):​c.874G>A​(p.Gly292Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G292D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.55

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 (HGNC:):

ACMG classification

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 chr21-46116028-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 21-46116027-G-A is Pathogenic according to our data. Variant chr21-46116027-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1351958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46116027-G-A is described in Lovd as [Pathogenic]. Variant chr21-46116027-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-46116027-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.874G>A	p.Gly292Ser	missense_variant	7/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.874G>A	p.Gly292Ser	missense_variant	7/28		NP_478054.2
COL6A2	NM_058175.3	c.874G>A	p.Gly292Ser	missense_variant	7/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.874G>A	p.Gly292Ser	missense_variant	7/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.874G>A	p.Gly292Ser	missense_variant	7/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.874G>A	p.Gly292Ser	missense_variant	6/27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.530G>A		non_coding_transcript_exon_variant	3/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL6A2 -related disorder (ClinVar ID: VCV001351958 / PMID: 29419890). The variant has been previously reported as de novo in a similarly affected individual (PMID: 29419890). Different missense changes at the same codon (p.Gly292Arg, p.Gly292Val) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000198473, VCV000476496). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2021	This sequence change replaces glycine with serine at codon 292 of the COL6A2 protein (p.Gly292Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with autosomal dominant COL6A2-related conditions (PMID: 29419890, 32403337). In at least one individual the variant was observed to be de novo. 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. 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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;H;H
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.92		Gain of phosphorylation at G292 (P = 0.0084);Gain of phosphorylation at G292 (P = 0.0084);Gain of phosphorylation at G292 (P = 0.0084);Gain of phosphorylation at G292 (P = 0.0084);
MVP		0.98
MPC		0.60
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs727502828; hg19: chr21-47535941;