rs140404854

Variant names:

• chr21-46114031-A-C
• NM_001849.4:c.759A>C

Your query was ambiguous. Multiple possible variants found:

• chr21-46114031-A-C
• chr21-46114031-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001849.4(COL6A2):​c.759A>C​(p.Glu253Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.759A>C	p.Glu253Asp	missense_variant	Exon 5 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.759A>C	p.Glu253Asp	missense_variant	Exon 5 of 28		NP_478054.2
COL6A2	NM_058175.3	c.759A>C	p.Glu253Asp	missense_variant	Exon 5 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.759A>C	p.Glu253Asp	missense_variant	Exon 5 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.759A>C	p.Glu253Asp	missense_variant	Exon 5 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.759A>C	p.Glu253Asp	missense_variant	Exon 4 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.415A>C		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Oct 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 253 of the COL6A2 protein (p.Glu253Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. 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 not expected to disrupt COL6A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	0.19
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.4	M;M;M;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.52
MutPred		0.46		Gain of glycosylation at S258 (P = 0.1465);Gain of glycosylation at S258 (P = 0.1465);Gain of glycosylation at S258 (P = 0.1465);Gain of glycosylation at S258 (P = 0.1465);
MVP		0.94
MPC		0.23
ClinPred		0.84	D
GERP RS		2.6
Varity_R		0.14
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-47533945;