chr2-237365901-C-A

Position:

• chr2-237365901-C-A

Variant summary

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

The NM_004369.4(COL6A3):​c.5635G>T​(p.Gly1879Cys) 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 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.856

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.5635G>T	p.Gly1879Cys	missense_variant	12/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5017G>T	p.Gly1673Cys	missense_variant	11/43		NP_476508.2
COL6A3	NM_057166.5	c.3814G>T	p.Gly1272Cys	missense_variant	9/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.5635G>T	p.Gly1879Cys	missense_variant	12/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.3814G>T	p.Gly1272Cys	missense_variant	9/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5017G>T	p.Gly1673Cys	missense_variant	11/43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.5635G>T (p.G1879C) alteration is located in exon 12 (coding exon 11) of the COL6A3 gene. This alteration results from a G to T substitution at nucleotide position 5635, causing the glycine (G) at amino acid position 1879 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.26	.;T;.;T;.
Eigen	Benign	0.013
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.091	N
LIST_S2	Uncertain	0.91	D;D;D;D;.
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D;D;D;.;D
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.68
MutPred		0.36		.;Gain of sheet (P = 0.0266);.;.;.;
MVP		0.66
MPC		0.66
ClinPred		0.71	D
GERP RS		3.4
Varity_R		0.18
gMVP		0.60

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: rs760603443; hg19: chr2-238274544;