NM_004369.4:c.3129C>T

Variant names:

• chr2-237374962-G-A
• rs12622093
• NM_004369.4:c.3129C>T

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.3129C>T​(p.Gly1043Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,658 control chromosomes in the GnomAD database, including 46,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3454 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42729 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.246
• Publications: 16 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=-0.5).
• BP6: Variant 2-237374962-G-A is Benign according to our data. Variant chr2-237374962-G-A is described in ClinVar as Benign. ClinVar VariationId is 94921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.246 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.268 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.3129C>T	p.Gly1043Gly	synonymous	Exon 8 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.2511C>T	p.Gly837Gly	synonymous	Exon 7 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.1308C>T	p.Gly436Gly	synonymous	Exon 5 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.3129C>T	p.Gly1043Gly	synonymous	Exon 8 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.1308C>T	p.Gly436Gly	synonymous	Exon 5 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000392004.7	TSL:1	c.2511C>T	p.Gly837Gly	synonymous	Exon 7 of 8	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31696 AN: 151802 Hom.: 3451 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.222

GnomAD2 exomes AF: 0.234 AC: 58220 AN: 248796 AF XY: 0.236

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.240

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.240 AC: 350363 AN: 1461738 Hom.: 42729 Cov.: 38 AF XY: 0.240 AC XY: 174243 AN XY: 727164

African (AFR) AF: 0.116 AC: 3869 AN: 33480

American (AMR) AF: 0.236 AC: 10553 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 5166 AN: 26136

East Asian (EAS) AF: 0.263 AC: 10422 AN: 39698

South Asian (SAS) AF: 0.233 AC: 20126 AN: 86258

European-Finnish (FIN) AF: 0.251 AC: 13375 AN: 53292

Middle Eastern (MID) AF: 0.238 AC: 1370 AN: 5768

European-Non Finnish (NFE) AF: 0.244 AC: 271602 AN: 1111992

Other (OTH) AF: 0.230 AC: 13880 AN: 60392

GnomAD4 genome AF: 0.209 AC: 31716 AN: 151920 Hom.: 3454 Cov.: 32 AF XY: 0.214 AC XY: 15871 AN XY: 74226

African (AFR) AF: 0.120 AC: 4995 AN: 41472

American (AMR) AF: 0.243 AC: 3704 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3464

East Asian (EAS) AF: 0.281 AC: 1437 AN: 5122

South Asian (SAS) AF: 0.250 AC: 1199 AN: 4796

European-Finnish (FIN) AF: 0.253 AC: 2662 AN: 10524

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16262 AN: 67968

Other (OTH) AF: 0.226 AC: 475 AN: 2106

Alfa AF: 0.230 Hom.: 9393

Bravo AF: 0.204

Asia WGS AF: 0.257 AC: 896 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.50
CADD	Benign	7.6
DANN	Benign	0.55
PhyloP100		0.25
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: rs12622093; hg19: chr2-238283605; COSMIC: COSV55078580; COSMIC: COSV55078580;