2-237371747-G-C

Variant names:

• chr2-237371747-G-C
• rs768522226
• NM_004369.4:c.4270C>G

Variant summary

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

The NM_004369.4(COL6A3):​c.4270C>G​(p.Arg1424Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,328 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00200

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=0.14433923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.4270C>G	p.Arg1424Gly	missense_variant	Exon 9 of 44	ENST00000295550.9	NP_004360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.4270C>G	p.Arg1424Gly	missense_variant	Exon 9 of 44	1	NM_004369.4	ENSP00000295550.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247246 Hom.: 0 AF XY: 0.00000748 AC XY: 1 AN XY: 133650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449328 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718964

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000457

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.22	.;T;.;T;.;.;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.85	D;D;D;D;.;D;D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	.;L;.;.;.;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N;N;N;.;N;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.025	D;D;D;.;D;D;T
Sift4G	Benign	0.46	T;T;T;T;T;T;T
Polyphen		0.64	P;B;.;.;P;.;.
Vest4		0.23
MutPred		0.38		.;Loss of sheet (P = 0.0457);.;.;.;.;.;
MVP		0.64
MPC		0.27
ClinPred		0.10	T
GERP RS		2.7
Varity_R		0.082
gMVP		0.41

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: rs768522226; hg19: chr2-238280390;