21-46115918-G-A

Position:

• chr21-46115918-G-A

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.848G>A​(p.Gly283Glu) variant causes a missense change. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G283R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.30

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 chr21-46115917-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-46115918-G-A is Pathogenic according to our data. Variant chr21-46115918-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46115918-G-A is described in Lovd as [Pathogenic]. Variant chr21-46115918-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.848G>A	p.Gly283Glu	missense_variant	6/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.848G>A	p.Gly283Glu	missense_variant	6/28		NP_478054.2
COL6A2	NM_058175.3	c.848G>A	p.Gly283Glu	missense_variant	6/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.848G>A	p.Gly283Glu	missense_variant	6/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.848G>A	p.Gly283Glu	missense_variant	6/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.848G>A	p.Gly283Glu	missense_variant	5/27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.504G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2019	This variant replaces the Glycine position in the GXY motif within the triple helical region of the COL6A2 protein; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29277723, 24038877) -

Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly283 amino acid residue in COL6A2. Other variant(s) that disrupt this residue have been observed in individuals with COL6A2-related conditions (PMID: 15689448, 24038877), which suggests that this may be a clinically significant amino acid residue. 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). 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. ClinVar contains an entry for this variant (Variation ID: 289114). This missense change has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 24038877). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 283 of the COL6A2 protein (p.Gly283Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;H;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		1.0
MutPred		0.93		Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);Loss of catalytic residue at P279 (P = 0.0722);
MVP		1.0
MPC		0.70
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs886044088; hg19: chr21-47535832;