chr2-237344509-C-T

Variant names:

• chr2-237344509-C-T
• rs34181055
• NM_004369.4:c.7509G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):​c.7509G>A​(p.Arg2503Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,614,188 control chromosomes in the GnomAD database, including 1,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (72 hom., cov: 32)
  • Exomes 𝑓: 0.034 (966 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.226
• Publications: 7 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=-0.78).
• BP6: Variant 2-237344509-C-T is Benign according to our data. Variant chr2-237344509-C-T is described in ClinVar as Benign. ClinVar VariationId is 94988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.226 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0246 (3753/152300) while in subpopulation SAS AF = 0.0388 (187/4816). AF 95% confidence interval is 0.0343. There are 72 homozygotes in GnomAd4. There are 1856 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AD,AR,SD gene

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.7509G>A	p.Arg2503Arg	synonymous	Exon 36 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.6891G>A	p.Arg2297Arg	synonymous	Exon 35 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.5688G>A	p.Arg1896Arg	synonymous	Exon 33 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.7509G>A	p.Arg2503Arg	synonymous	Exon 36 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.5688G>A	p.Arg1896Arg	synonymous	Exon 33 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.6891G>A	p.Arg2297Arg	synonymous	Exon 35 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3755 AN: 152182 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.0418

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0287 AC: 7212 AN: 251418 AF XY: 0.0305

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.0104

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0339 AC: 49616 AN: 1461888 Hom.: 966 Cov.: 34 AF XY: 0.0342 AC XY: 24858 AN XY: 727244

African (AFR) AF: 0.00454 AC: 152 AN: 33480

American (AMR) AF: 0.0128 AC: 574 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 715 AN: 26136

East Asian (EAS) AF: 0.00992 AC: 394 AN: 39700

South Asian (SAS) AF: 0.0395 AC: 3405 AN: 86258

European-Finnish (FIN) AF: 0.0399 AC: 2129 AN: 53420

Middle Eastern (MID) AF: 0.0121 AC: 70 AN: 5768

European-Non Finnish (NFE) AF: 0.0362 AC: 40295 AN: 1112008

Other (OTH) AF: 0.0312 AC: 1882 AN: 60396

GnomAD4 genome AF: 0.0246 AC: 3753 AN: 152300 Hom.: 72 Cov.: 32 AF XY: 0.0249 AC XY: 1856 AN XY: 74462

African (AFR) AF: 0.00633 AC: 263 AN: 41572

American (AMR) AF: 0.0152 AC: 232 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.00946 AC: 49 AN: 5178

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4816

European-Finnish (FIN) AF: 0.0418 AC: 444 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0351 AC: 2388 AN: 68030

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.0309 Hom.: 36

Bravo AF: 0.0224

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0311

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	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	-0.78
CADD	Benign	1.8
DANN	Benign	0.48
PhyloP100		0.23
PromoterAI		-0.0070	Neutral
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34181055; hg19: chr2-238253152; COSMIC: COSV55108460; COSMIC: COSV55108460;