2-237340921-T-G

Variant names:

• chr2-237340921-T-G
• rs80193928
• NM_004369.4:c.7995A>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.7995A>C​(p.Ala2665Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,613,330 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2665A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (82 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (83 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -7.21
• Publications: 2 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=-0.92).
• BP6: Variant 2-237340921-T-G is Benign according to our data. Variant chr2-237340921-T-G is described in ClinVar as Benign. ClinVar VariationId is 94999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0555 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.7995A>C	p.Ala2665Ala	synonymous	Exon 38 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7377A>C	p.Ala2459Ala	synonymous	Exon 37 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6174A>C	p.Ala2058Ala	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.7995A>C	p.Ala2665Ala	synonymous	Exon 38 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6174A>C	p.Ala2058Ala	synonymous	Exon 35 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7377A>C	p.Ala2459Ala	synonymous	Exon 37 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2560 AN: 152184 Hom.: 78 Cov.: 32

Gnomad AFR AF: 0.0572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00765

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00500 AC: 1256 AN: 250950 AF XY: 0.00378

Gnomad AFR exome AF: 0.0583

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000723

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00219 AC: 3204 AN: 1461028 Hom.: 83 Cov.: 33 AF XY: 0.00195 AC XY: 1414 AN XY: 726636

African (AFR) AF: 0.0586 AC: 1960 AN: 33466

American (AMR) AF: 0.00581 AC: 260 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86230

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53410

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5766

European-Non Finnish (NFE) AF: 0.000481 AC: 535 AN: 1111306

Other (OTH) AF: 0.00567 AC: 342 AN: 60354

GnomAD4 genome AF: 0.0169 AC: 2578 AN: 152302 Hom.: 82 Cov.: 32 AF XY: 0.0160 AC XY: 1195 AN XY: 74474

African (AFR) AF: 0.0574 AC: 2386 AN: 41550

American (AMR) AF: 0.00764 AC: 117 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68022

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00645 Hom.: 15

Bravo AF: 0.0191

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00113

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	-0.92
CADD	Benign	0.034
DANN	Benign	0.39
PhyloP100		-7.2
Mutation Taster		=86/14	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: rs80193928; hg19: chr2-238249564;