NM_004369.4:c.4311T>C

Variant names:

• chr2-237369152-A-G
• rs2646260
• NM_004369.4:c.4311T>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.4311T>C​(p.Ile1437Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,612,410 control chromosomes in the GnomAD database, including 62,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10786 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51459 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.58
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-237369152-A-G is Benign according to our data. Variant chr2-237369152-A-G is described in ClinVar as Benign. ClinVar VariationId is 94933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 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.4311T>C	p.Ile1437Ile	synonymous	Exon 10 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.3693T>C	p.Ile1231Ile	synonymous	Exon 9 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.2490T>C	p.Ile830Ile	synonymous	Exon 7 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.4311T>C	p.Ile1437Ile	synonymous	Exon 10 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.2490T>C	p.Ile830Ile	synonymous	Exon 7 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.3693T>C	p.Ile1231Ile	synonymous	Exon 9 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52284 AN: 152006 Hom.: 10738 Cov.: 32

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.286 AC: 70772 AN: 247474 AF XY: 0.278

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.295

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.257 AC: 375733 AN: 1460286 Hom.: 51459 Cov.: 39 AF XY: 0.257 AC XY: 186527 AN XY: 726554

African (AFR) AF: 0.593 AC: 19868 AN: 33480

American (AMR) AF: 0.345 AC: 15421 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5774 AN: 26134

East Asian (EAS) AF: 0.286 AC: 11365 AN: 39698

South Asian (SAS) AF: 0.294 AC: 25343 AN: 86252

European-Finnish (FIN) AF: 0.222 AC: 11545 AN: 51976

Middle Eastern (MID) AF: 0.281 AC: 1621 AN: 5768

European-Non Finnish (NFE) AF: 0.241 AC: 268374 AN: 1111888

Other (OTH) AF: 0.272 AC: 16422 AN: 60380

GnomAD4 genome AF: 0.344 AC: 52401 AN: 152124 Hom.: 10786 Cov.: 32 AF XY: 0.345 AC XY: 25633 AN XY: 74374

African (AFR) AF: 0.578 AC: 23957 AN: 41482

American (AMR) AF: 0.336 AC: 5142 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 862 AN: 3470

East Asian (EAS) AF: 0.297 AC: 1529 AN: 5156

South Asian (SAS) AF: 0.310 AC: 1494 AN: 4826

European-Finnish (FIN) AF: 0.227 AC: 2406 AN: 10596

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16099 AN: 67980

Other (OTH) AF: 0.324 AC: 686 AN: 2116

Alfa AF: 0.256 Hom.: 9354

Bravo AF: 0.362

Asia WGS AF: 0.339 AC: 1183 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.81
CADD	Benign	2.4
DANN	Benign	0.67
PhyloP100		-1.6
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: rs2646260; hg19: chr2-238277795; COSMIC: COSV55080982; COSMIC: COSV55080982;