chr2-237336280-C-T

Variant names:

• chr2-237336280-C-T
• rs11683438
• NM_004369.4:c.8820G>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.8820G>A​(p.Thr2940Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0943 in 1,614,054 control chromosomes in the GnomAD database, including 8,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (477 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7630 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.08
• Publications: 10 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=-0.7).
• BP6: Variant 2-237336280-C-T is Benign according to our data. Variant chr2-237336280-C-T is described in ClinVar as Benign. ClinVar VariationId is 95009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.1 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.8820G>A	p.Thr2940Thr	synonymous	Exon 40 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.8202G>A	p.Thr2734Thr	synonymous	Exon 39 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6999G>A	p.Thr2333Thr	synonymous	Exon 37 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.8820G>A	p.Thr2940Thr	synonymous	Exon 40 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6999G>A	p.Thr2333Thr	synonymous	Exon 37 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.8202G>A	p.Thr2734Thr	synonymous	Exon 39 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10428 AN: 152170 Hom.: 477 Cov.: 33

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0911

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0638

GnomAD2 exomes AF: 0.0747 AC: 18718 AN: 250668 AF XY: 0.0770

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0390

Gnomad ASJ exome AF: 0.107

Gnomad EAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0939

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0742

GnomAD4 exome AF: 0.0970 AC: 141854 AN: 1461766 Hom.: 7630 Cov.: 31 AF XY: 0.0961 AC XY: 69884 AN XY: 727186

African (AFR) AF: 0.0158 AC: 528 AN: 33478

American (AMR) AF: 0.0412 AC: 1844 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2904 AN: 26134

East Asian (EAS) AF: 0.00967 AC: 384 AN: 39698

South Asian (SAS) AF: 0.0649 AC: 5600 AN: 86258

European-Finnish (FIN) AF: 0.0931 AC: 4967 AN: 53358

Middle Eastern (MID) AF: 0.0462 AC: 266 AN: 5762

European-Non Finnish (NFE) AF: 0.108 AC: 119993 AN: 1111964

Other (OTH) AF: 0.0889 AC: 5368 AN: 60390

GnomAD4 genome AF: 0.0684 AC: 10422 AN: 152288 Hom.: 477 Cov.: 33 AF XY: 0.0668 AC XY: 4973 AN XY: 74460

African (AFR) AF: 0.0188 AC: 780 AN: 41570

American (AMR) AF: 0.0486 AC: 743 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3470

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5184

South Asian (SAS) AF: 0.0636 AC: 307 AN: 4828

European-Finnish (FIN) AF: 0.0911 AC: 966 AN: 10602

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6942 AN: 68030

Other (OTH) AF: 0.0627 AC: 132 AN: 2106

Alfa AF: 0.0902 Hom.: 427

Bravo AF: 0.0645

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0995

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.4
DANN	Benign	0.47
PhyloP100		-1.1
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: rs11683438; hg19: chr2-238244923; COSMIC: COSV55108407; COSMIC: COSV55108407;