rs369537287

chr2-237340963-C-Gchr2-237340963-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004369.4(COL6A3):c.7953G>C(p.Met2651Ile) 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 benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.446

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051797807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.7953G>C	p.Met2651Ile	missense_variant	38/44	ENST00000295550.9
COL6A3	NM_057167.4	c.7335G>C	p.Met2445Ile	missense_variant	37/43
COL6A3	NM_057166.5	c.6132G>C	p.Met2044Ile	missense_variant	35/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7953G>C	p.Met2651Ile	missense_variant	38/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.2
Dann	Benign	0.93
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.73	T;T;T;T;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.052	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.88	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.2	N;N;N;.;N
REVEL	Benign	0.050
Sift	Benign	0.55	T;T;T;.;T
Sift4G	Benign	0.83	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.095
MutPred		0.45		.;Loss of loop (P = 0.0374);.;.;.;
MVP		0.17
MPC		0.16
ClinPred		0.074	T
GERP RS		0.60
Varity_R		0.059
gMVP		0.26

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: rs369537287; hg19: chr2-238249606;