2-237340987-C-T

Variant names:

• chr2-237340987-C-T
• rs4433949
• NM_004369.4:c.7929G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7929G>A​(p.Ala2643Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,613,868 control chromosomes in the GnomAD database, including 131,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2643A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.37 (11313 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119955 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.131
• Publications: 26 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AR, SD, AD 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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 2-237340987-C-T is Benign according to our data. Variant chr2-237340987-C-T is described in ClinVar as Benign. ClinVar VariationId is 94998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.131 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 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.7929G>A	p.Ala2643Ala	synonymous	Exon 38 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7311G>A	p.Ala2437Ala	synonymous	Exon 37 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6108G>A	p.Ala2036Ala	synonymous	Exon 35 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7929G>A	p.Ala2643Ala	synonymous	Exon 38 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6108G>A	p.Ala2036Ala	synonymous	Exon 35 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7311G>A	p.Ala2437Ala	synonymous	Exon 37 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56772 AN: 151910 Hom.: 11317 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.363

Gnomad ASJ AF: 0.454

Gnomad EAS AF: 0.477

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.508

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.403

GnomAD2 exomes AF: 0.396 AC: 99511 AN: 250988 AF XY: 0.400

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.442

Gnomad EAS exome AF: 0.476

Gnomad FIN exome AF: 0.497

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.402 AC: 587666 AN: 1461842 Hom.: 119955 Cov.: 68 AF XY: 0.401 AC XY: 291804 AN XY: 727222

African (AFR) AF: 0.249 AC: 8321 AN: 33480

American (AMR) AF: 0.324 AC: 14469 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 11668 AN: 26134

East Asian (EAS) AF: 0.505 AC: 20041 AN: 39700

South Asian (SAS) AF: 0.334 AC: 28786 AN: 86254

European-Finnish (FIN) AF: 0.491 AC: 26215 AN: 53418

Middle Eastern (MID) AF: 0.459 AC: 2645 AN: 5768

European-Non Finnish (NFE) AF: 0.406 AC: 451390 AN: 1111968

Other (OTH) AF: 0.400 AC: 24131 AN: 60396

GnomAD4 genome AF: 0.374 AC: 56783 AN: 152026 Hom.: 11313 Cov.: 32 AF XY: 0.379 AC XY: 28173 AN XY: 74296

African (AFR) AF: 0.252 AC: 10471 AN: 41472

American (AMR) AF: 0.362 AC: 5541 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.454 AC: 1574 AN: 3470

East Asian (EAS) AF: 0.477 AC: 2452 AN: 5140

South Asian (SAS) AF: 0.334 AC: 1608 AN: 4808

European-Finnish (FIN) AF: 0.508 AC: 5374 AN: 10570

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28284 AN: 67954

Other (OTH) AF: 0.402 AC: 848 AN: 2112

Alfa AF: 0.390 Hom.: 16148

Bravo AF: 0.358

Asia WGS AF: 0.384 AC: 1336 AN: 3478

EpiCase AF: 0.417

EpiControl AF: 0.424

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Dystonia 27 (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.3
DANN	Benign	0.57
PhyloP100		-0.13
Mutation Taster		=99/1	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: rs4433949; hg19: chr2-238249630; COSMIC: COSV55080044; COSMIC: COSV55080044;