rs2291795

Variant names:

• chr2-237344422-C-T
• rs2291795
• NM_004369.4:c.7596G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7596G>A​(p.Lys2532Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,614,090 control chromosomes in the GnomAD database, including 12,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1390 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11269 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.19
• Publications: 17 publications found

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]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-237344422-C-T is Benign according to our data. Variant chr2-237344422-C-T is described in ClinVar as Benign. ClinVar VariationId is 94990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.7596G>A	p.Lys2532Lys	synonymous	Exon 36 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.6978G>A	p.Lys2326Lys	synonymous	Exon 35 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.5775G>A	p.Lys1925Lys	synonymous	Exon 33 of 41	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7596G>A	p.Lys2532Lys	synonymous	Exon 36 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5775G>A	p.Lys1925Lys	synonymous	Exon 33 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6978G>A	p.Lys2326Lys	synonymous	Exon 35 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19866 AN: 152092 Hom.: 1377 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.0846

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.128 AC: 32192 AN: 251394 AF XY: 0.128

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.0863

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.121 AC: 176814 AN: 1461880 Hom.: 11269 Cov.: 33 AF XY: 0.122 AC XY: 88755 AN XY: 727242

African (AFR) AF: 0.170 AC: 5684 AN: 33480

American (AMR) AF: 0.129 AC: 5753 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3145 AN: 26136

East Asian (EAS) AF: 0.164 AC: 6498 AN: 39700

South Asian (SAS) AF: 0.178 AC: 15348 AN: 86256

European-Finnish (FIN) AF: 0.0894 AC: 4774 AN: 53420

Middle Eastern (MID) AF: 0.118 AC: 681 AN: 5768

European-Non Finnish (NFE) AF: 0.114 AC: 126603 AN: 1112002

Other (OTH) AF: 0.138 AC: 8328 AN: 60394

GnomAD4 genome AF: 0.131 AC: 19918 AN: 152210 Hom.: 1390 Cov.: 32 AF XY: 0.129 AC XY: 9574 AN XY: 74412

African (AFR) AF: 0.170 AC: 7078 AN: 41520

American (AMR) AF: 0.122 AC: 1864 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3470

East Asian (EAS) AF: 0.183 AC: 944 AN: 5170

South Asian (SAS) AF: 0.179 AC: 862 AN: 4822

European-Finnish (FIN) AF: 0.0846 AC: 898 AN: 10610

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7477 AN: 68004

Other (OTH) AF: 0.123 AC: 259 AN: 2110

Alfa AF: 0.117 Hom.: 2050

Bravo AF: 0.137

Asia WGS AF: 0.196 AC: 683 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.111

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.1
DANN	Benign	0.51
PhyloP100		1.2
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2291795; hg19: chr2-238253065; COSMIC: COSV55084005; COSMIC: COSV55084005;