2-237350171-C-G

Variant names:

• chr2-237350171-C-G
• rs3790993
• NM_004369.4:c.6855G>C

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.6855G>C​(p.Gly2285Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,613,458 control chromosomes in the GnomAD database, including 235,064 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. G2285G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.56 (23792 hom., cov: 31)
  • Exomes 𝑓: 0.54 (211272 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.233
• Publications: 22 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=-0.82).
• BP6: Variant 2-237350171-C-G is Benign according to our data. Variant chr2-237350171-C-G is described in ClinVar as Benign. ClinVar VariationId is 94968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.233 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 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.6855G>C	p.Gly2285Gly	synonymous	Exon 28 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6237G>C	p.Gly2079Gly	synonymous	Exon 27 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5034G>C	p.Gly1678Gly	synonymous	Exon 25 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.6855G>C	p.Gly2285Gly	synonymous	Exon 28 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5034G>C	p.Gly1678Gly	synonymous	Exon 25 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6237G>C	p.Gly2079Gly	synonymous	Exon 27 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84468 AN: 151800 Hom.: 23760 Cov.: 31

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.556

GnomAD2 exomes AF: 0.542 AC: 136333 AN: 251332 AF XY: 0.543

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.460

Gnomad ASJ exome AF: 0.576

Gnomad EAS exome AF: 0.654

Gnomad FIN exome AF: 0.586

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.560

GnomAD4 exome AF: 0.536 AC: 783904 AN: 1461540 Hom.: 211272 Cov.: 51 AF XY: 0.536 AC XY: 389581 AN XY: 727108

African (AFR) AF: 0.584 AC: 19550 AN: 33478

American (AMR) AF: 0.466 AC: 20833 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 14941 AN: 26134

East Asian (EAS) AF: 0.672 AC: 26690 AN: 39698

South Asian (SAS) AF: 0.515 AC: 44409 AN: 86250

European-Finnish (FIN) AF: 0.583 AC: 31130 AN: 53378

Middle Eastern (MID) AF: 0.593 AC: 3422 AN: 5768

European-Non Finnish (NFE) AF: 0.530 AC: 589371 AN: 1111734

Other (OTH) AF: 0.556 AC: 33558 AN: 60378

GnomAD4 genome AF: 0.557 AC: 84557 AN: 151918 Hom.: 23792 Cov.: 31 AF XY: 0.556 AC XY: 41296 AN XY: 74220

African (AFR) AF: 0.586 AC: 24281 AN: 41408

American (AMR) AF: 0.503 AC: 7684 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2016 AN: 3470

East Asian (EAS) AF: 0.664 AC: 3413 AN: 5140

South Asian (SAS) AF: 0.515 AC: 2474 AN: 4808

European-Finnish (FIN) AF: 0.594 AC: 6269 AN: 10554

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.537 AC: 36477 AN: 67950

Other (OTH) AF: 0.561 AC: 1184 AN: 2112

Alfa AF: 0.515 Hom.: 5735

Bravo AF: 0.552

Asia WGS AF: 0.601 AC: 2091 AN: 3478

EpiCase AF: 0.542

EpiControl AF: 0.544

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	-0.82
CADD	Benign	7.0
DANN	Benign	0.18
PhyloP100		0.23
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.070		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: rs3790993; hg19: chr2-238258814; COSMIC: COSV55078615;