2-237359382-G-C

Variant names:

• chr2-237359382-G-C
• NM_004369.4:c.6289C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_004369.4(COL6A3):​c.6289C>G​(p.Arg2097Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.92

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Collagen-like 1 (size 59) in uniprot entity CO6A3_HUMAN there are 31 pathogenic changes around while only 0 benign (100%) in NM_004369.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6289C>G	p.Arg2097Gly	missense_variant	Exon 18 of 44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5671C>G	p.Arg1891Gly	missense_variant	Exon 17 of 43		NP_476508.2
COL6A3	NM_057166.5	c.4468C>G	p.Arg1490Gly	missense_variant	Exon 15 of 41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6289C>G	p.Arg2097Gly	missense_variant	Exon 18 of 44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4468C>G	p.Arg1490Gly	missense_variant	Exon 15 of 41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5671C>G	p.Arg1891Gly	missense_variant	Exon 17 of 43	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461486 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727026

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	.;D;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	.;M;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D;D;D;.;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.73
MutPred		0.47		.;Loss of solvent accessibility (P = 0.0159);.;.;.;
MVP		0.95
MPC		0.71
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-238268025;