2-237368568-C-A

Position:

• chr2-237368568-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000295550.9(COL6A3):​c.4895G>T​(p.Arg1632Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R1632W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A3 ENST00000295550.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.909

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069165856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.4895G>T	p.Arg1632Leu	missense_variant	10/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.4277G>T	p.Arg1426Leu	missense_variant	9/43		NP_476508.2
COL6A3	NM_057166.5	c.3074G>T	p.Arg1025Leu	missense_variant	7/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4895G>T	p.Arg1632Leu	missense_variant	10/44	1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.3074G>T	p.Arg1025Leu	missense_variant	7/41	1		ENSP00000418285
COL6A3	ENST00000353578.9	c.4277G>T	p.Arg1426Leu	missense_variant	9/43	5		ENSP00000315873
COL6A3	ENST00000684597.1	c.227G>T	p.Arg76Leu	missense_variant	2/3			ENSP00000508021

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	3.6
DANN	Benign	0.81
DEOGEN2	Benign	0.12	.;T;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.75	T;T;T;T;.
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.069	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	.;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.010	N;N;N;.;N
REVEL	Benign	0.067
Sift	Benign	0.44	T;T;T;.;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.16	B;B;.;.;B
Vest4		0.15
MutPred		0.34		.;Gain of relative solvent accessibility (P = 0.0275);.;.;.;
MVP		0.55
MPC		0.20
ClinPred		0.077	T
GERP RS		-0.80
Varity_R		0.072
gMVP		0.38

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: rs111231885; hg19: chr2-238277211;