2-237344689-G-A

Variant names:

• chr2-237344689-G-A
• rs10084221
• NM_004369.4:c.7329C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004369.4(COL6A3):​c.7329C>T​(p.Ala2443Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,609,996 control chromosomes in the GnomAD database, including 1,654 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (687 hom., cov: 32)
  • Exomes 𝑓: 0.023 (967 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.192
• Publications: 8 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: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-237344689-G-A is Benign according to our data. Variant chr2-237344689-G-A is described in ClinVar as Benign. ClinVar VariationId is 94985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.192 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	NM_004369.4	MANE Select	c.7329C>T	p.Ala2443Ala	synonymous	Exon 36 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.6711C>T	p.Ala2237Ala	synonymous	Exon 35 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.5508C>T	p.Ala1836Ala	synonymous	Exon 33 of 41	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7329C>T	p.Ala2443Ala	synonymous	Exon 36 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.5508C>T	p.Ala1836Ala	synonymous	Exon 33 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.6711C>T	p.Ala2237Ala	synonymous	Exon 35 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9673 AN: 151992 Hom.: 687 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0365

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00425

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0603

GnomAD2 exomes AF: 0.0320 AC: 7974 AN: 249010 AF XY: 0.0296

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0427

Gnomad EAS exome AF: 0.00408

Gnomad FIN exome AF: 0.00763

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0230 AC: 33544 AN: 1457886 Hom.: 967 Cov.: 34 AF XY: 0.0227 AC XY: 16441 AN XY: 724732

African (AFR) AF: 0.187 AC: 6231 AN: 33284

American (AMR) AF: 0.0258 AC: 1146 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.0431 AC: 1118 AN: 25966

East Asian (EAS) AF: 0.00182 AC: 72 AN: 39632

South Asian (SAS) AF: 0.0260 AC: 2235 AN: 86054

European-Finnish (FIN) AF: 0.00929 AC: 494 AN: 53188

Middle Eastern (MID) AF: 0.0632 AC: 363 AN: 5748

European-Non Finnish (NFE) AF: 0.0180 AC: 19917 AN: 1109412

Other (OTH) AF: 0.0327 AC: 1968 AN: 60164

GnomAD4 genome AF: 0.0637 AC: 9683 AN: 152110 Hom.: 687 Cov.: 32 AF XY: 0.0612 AC XY: 4548 AN XY: 74354

African (AFR) AF: 0.176 AC: 7293 AN: 41458

American (AMR) AF: 0.0364 AC: 556 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5168

South Asian (SAS) AF: 0.0237 AC: 114 AN: 4806

European-Finnish (FIN) AF: 0.00754 AC: 80 AN: 10606

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0196 AC: 1332 AN: 68008

Other (OTH) AF: 0.0597 AC: 126 AN: 2110

Alfa AF: 0.0442 Hom.: 156

Bravo AF: 0.0717

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0253

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.42
CADD	Benign	7.0
DANN	Benign	0.72
PhyloP100		0.19
PromoterAI		-0.027	Neutral
Mutation Taster		=99/1	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: rs10084221; hg19: chr2-238253332;