rs267606747

Positions:

• chr21-46126144-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001849.4(COL6A2):​c.2329T>C​(p.Cys777Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,458,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C777C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain VWFA 2 (size 190) in uniprot entity CO6A2_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 21-46126144-T-C is Pathogenic according to our data. Variant chr21-46126144-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46126144-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2329T>C	p.Cys777Arg	missense_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2329T>C	p.Cys777Arg	missense_variant	26/28		NP_478054.2
COL6A2	NM_058175.3	c.2329T>C	p.Cys777Arg	missense_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2329T>C	p.Cys777Arg	missense_variant	26/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2329T>C	p.Cys777Arg	missense_variant	26/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2329T>C	p.Cys777Arg	missense_variant	25/27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248430 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458810 Hom.: 0 Cov.: 37 AF XY: 0.00000551 AC XY: 4 AN XY: 725804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2022	This variant is present in population databases (rs267606747, gnomAD 0.003%). For these reasons, this variant has been classified as 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. ClinVar contains an entry for this variant (Variation ID: 17166). This missense change has been observed in individuals with autosomal recessive Ullrich congenital muscular dystrophy (PMID: 15689448, 19564581, 22075033, 23940025). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 777 of the COL6A2 protein (p.Cys777Arg). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 20, 2021	- -

Ullrich congenital muscular dystrophy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 07, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.60	D;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;.;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-10	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.83		Gain of disorder (P = 0.0137);Gain of disorder (P = 0.0137);Gain of disorder (P = 0.0137);Gain of disorder (P = 0.0137);
MVP		0.98
MPC		0.79
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.97
gMVP		0.95

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: rs267606747; hg19: chr21-47546058; COSMIC: COSV55998575; COSMIC: COSV55998575;