chr2-237341074-G-A

Variant names:

• chr2-237341074-G-A
• rs34558385
• NM_004369.4:c.7842C>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.7842C>T​(p.Ser2614Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0945 in 1,613,912 control chromosomes in the GnomAD database, including 8,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (477 hom., cov: 31)
  • Exomes 𝑓: 0.097 (7653 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.934
• 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=-0.47).
• BP6: Variant 2-237341074-G-A is Benign according to our data. Variant chr2-237341074-G-A is described in ClinVar as Benign. ClinVar VariationId is 94997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.934 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.7842C>T	p.Ser2614Ser	synonymous	Exon 38 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7224C>T	p.Ser2408Ser	synonymous	Exon 37 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6021C>T	p.Ser2007Ser	synonymous	Exon 35 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.7842C>T	p.Ser2614Ser	synonymous	Exon 38 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6021C>T	p.Ser2007Ser	synonymous	Exon 35 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7224C>T	p.Ser2408Ser	synonymous	Exon 37 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10443 AN: 152020 Hom.: 477 Cov.: 31

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.0488

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00946

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0918

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.0649

GnomAD2 exomes AF: 0.0749 AC: 18737 AN: 250064 AF XY: 0.0773

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.0391

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.0100

Gnomad FIN exome AF: 0.0948

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0751

GnomAD4 exome AF: 0.0972 AC: 142019 AN: 1461774 Hom.: 7653 Cov.: 35 AF XY: 0.0962 AC XY: 69955 AN XY: 727194

African (AFR) AF: 0.0159 AC: 531 AN: 33480

American (AMR) AF: 0.0415 AC: 1857 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2945 AN: 26136

East Asian (EAS) AF: 0.00967 AC: 384 AN: 39700

South Asian (SAS) AF: 0.0649 AC: 5601 AN: 86258

European-Finnish (FIN) AF: 0.0935 AC: 4984 AN: 53322

Middle Eastern (MID) AF: 0.0525 AC: 303 AN: 5768

European-Non Finnish (NFE) AF: 0.108 AC: 120023 AN: 1111994

Other (OTH) AF: 0.0893 AC: 5391 AN: 60392

GnomAD4 genome AF: 0.0686 AC: 10437 AN: 152138 Hom.: 477 Cov.: 31 AF XY: 0.0670 AC XY: 4980 AN XY: 74364

African (AFR) AF: 0.0189 AC: 783 AN: 41524

American (AMR) AF: 0.0488 AC: 746 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3468

East Asian (EAS) AF: 0.00948 AC: 49 AN: 5170

South Asian (SAS) AF: 0.0639 AC: 307 AN: 4806

European-Finnish (FIN) AF: 0.0918 AC: 971 AN: 10572

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.102 AC: 6934 AN: 67976

Other (OTH) AF: 0.0638 AC: 135 AN: 2116

Alfa AF: 0.0748 Hom.: 197

Bravo AF: 0.0646

Asia WGS AF: 0.0440 AC: 152 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
-	-	8	not specified (8)
-	-	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
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.6
DANN	Benign	0.64
PhyloP100		-0.93
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34558385; hg19: chr2-238249717; COSMIC: COSV55092883; COSMIC: COSV55092883;