2-237347812-G-C

Position:

• chr2-237347812-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000295550.9(COL6A3):​c.7024C>G​(p.Arg2342Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2342Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 ENST00000295550.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7024C>G	p.Arg2342Gly	missense_variant	31/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6406C>G	p.Arg2136Gly	missense_variant	30/43		NP_476508.2
COL6A3	NM_057166.5	c.5203C>G	p.Arg1735Gly	missense_variant	28/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7024C>G	p.Arg2342Gly	missense_variant	31/44	1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.5203C>G	p.Arg1735Gly	missense_variant	28/41	1		ENSP00000418285
COL6A3	ENST00000353578.9	c.6406C>G	p.Arg2136Gly	missense_variant	30/43	5		ENSP00000315873
COL6A3	ENST00000491769.1	n.1278C>G		non_coding_transcript_exon_variant	8/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;.;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;.
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.5	.;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D;D;D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0060	D;D;D;.;D
Sift4G	Uncertain	0.037	D;D;D;T;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.68
MutPred		0.43		.;Loss of methylation at R2342 (P = 0.0065);.;.;.;
MVP		0.90
MPC		0.19
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs886043113; hg19: chr2-238256455;