chr2-237363239-T-TA

Variant names:

• chr2-237363239-T-TA
• rs11385011
• NM_004369.4:c.6063+13dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.6063+13dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,610,626 control chromosomes in the GnomAD database, including 27,850 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3005 hom., cov: 27)
  • Exomes 𝑓: 0.18 (24845 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.523
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 2-237363239-T-TA is Benign according to our data. Variant chr2-237363239-T-TA is described in ClinVar as Benign. ClinVar VariationId is 94950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 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.6063+13dupT		intron	N/A	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.5445+13dupT		intron	N/A	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.4242+13dupT		intron	N/A	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.6063+13_6063+14insT		intron	N/A	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.4242+13_4242+14insT		intron	N/A	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.5445+13_5445+14insT		intron	N/A	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29119 AN: 150860 Hom.: 3002 Cov.: 27

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.00391

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.155 AC: 38978 AN: 251318 AF XY: 0.155

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0939

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.00304

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.158

GnomAD4 exome AF: 0.180 AC: 262175 AN: 1459648 Hom.: 24845 Cov.: 33 AF XY: 0.177 AC XY: 128797 AN XY: 726216

African (AFR) AF: 0.254 AC: 8483 AN: 33420

American (AMR) AF: 0.100 AC: 4486 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4467 AN: 26086

East Asian (EAS) AF: 0.00182 AC: 72 AN: 39620

South Asian (SAS) AF: 0.110 AC: 9515 AN: 86218

European-Finnish (FIN) AF: 0.180 AC: 9602 AN: 53268

Middle Eastern (MID) AF: 0.162 AC: 933 AN: 5758

European-Non Finnish (NFE) AF: 0.193 AC: 214252 AN: 1110262

Other (OTH) AF: 0.172 AC: 10365 AN: 60306

GnomAD4 genome AF: 0.193 AC: 29151 AN: 150978 Hom.: 3005 Cov.: 27 AF XY: 0.190 AC XY: 13985 AN XY: 73658

African (AFR) AF: 0.248 AC: 10211 AN: 41096

American (AMR) AF: 0.156 AC: 2366 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 647 AN: 3468

East Asian (EAS) AF: 0.00392 AC: 20 AN: 5108

South Asian (SAS) AF: 0.112 AC: 531 AN: 4740

European-Finnish (FIN) AF: 0.180 AC: 1855 AN: 10318

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12924 AN: 67812

Other (OTH) AF: 0.198 AC: 413 AN: 2088

Alfa AF: 0.105 Hom.: 215

Asia WGS AF: 0.0580 AC: 206 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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
PhyloP100		-0.52
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: rs11385011; hg19: chr2-238271882;