rs1555875749

Positions:

• chr21-46125988-G-T
• chr21-46125988-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001849.4(COL6A2):​c.2173G>T​(p.Val725Leu) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V725V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.76

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2173G>T	p.Val725Leu	missense_variant	26/28	ENST00000300527.9
COL6A2	NM_058174.3	c.2173G>T	p.Val725Leu	missense_variant	26/28	ENST00000397763.6
COL6A2	NM_058175.3	c.2173G>T	p.Val725Leu	missense_variant	26/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2173G>T	p.Val725Leu	missense_variant	26/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.2173G>T	p.Val725Leu	missense_variant	26/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.2173G>T	p.Val725Leu	missense_variant	25/27	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 78

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 725 of the COL6A2 protein (p.Val725Leu). 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. ClinVar contains an entry for this variant (Variation ID: 476463). 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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.046	D;D;D;D
Sift4G	Uncertain	0.031	D;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.68
MutPred		0.50		Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);Loss of methylation at K722 (P = 0.0805);
MVP		0.95
MPC		0.60
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.52
gMVP		0.89

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: rs1555875749; hg19: chr21-47545902;