2-237324840-G-A

Variant names:

• chr2-237324840-G-A
• rs13032404
• NM_004369.4:c.9494-26C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.9494-26C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,610,050 control chromosomes in the GnomAD database, including 75,182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.26 (5743 hom., cov: 31)
  • Exomes 𝑓: 0.31 (69439 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.91
• Publications: 9 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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-237324840-G-A is Benign according to our data. Variant chr2-237324840-G-A is described in ClinVar as Benign. ClinVar VariationId is 95022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 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.9494-26C>T		intron	N/A	NP_004360.2
	COL6A3	NM_057167.4		c.8876-26C>T		intron	N/A	NP_476508.2
	COL6A3	NM_057166.5		c.7673-26C>T		intron	N/A	NP_476507.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.9494-26C>T		intron	N/A	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.7673-26C>T		intron	N/A	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.8876-26C>T		intron	N/A	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39597 AN: 151772 Hom.: 5748 Cov.: 31

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.321

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.265

GnomAD2 exomes AF: 0.290 AC: 71466 AN: 246308 AF XY: 0.294

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.317

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.305 AC: 445269 AN: 1458160 Hom.: 69439 Cov.: 34 AF XY: 0.305 AC XY: 221349 AN XY: 725456

African (AFR) AF: 0.125 AC: 4172 AN: 33450

American (AMR) AF: 0.256 AC: 11463 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 8287 AN: 26118

East Asian (EAS) AF: 0.389 AC: 15442 AN: 39686

South Asian (SAS) AF: 0.257 AC: 22177 AN: 86218

European-Finnish (FIN) AF: 0.348 AC: 17957 AN: 51632

Middle Eastern (MID) AF: 0.288 AC: 1657 AN: 5756

European-Non Finnish (NFE) AF: 0.312 AC: 346628 AN: 1110296

Other (OTH) AF: 0.290 AC: 17486 AN: 60304

GnomAD4 genome AF: 0.261 AC: 39594 AN: 151890 Hom.: 5743 Cov.: 31 AF XY: 0.263 AC XY: 19539 AN XY: 74232

African (AFR) AF: 0.130 AC: 5405 AN: 41452

American (AMR) AF: 0.266 AC: 4056 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1152 AN: 3464

East Asian (EAS) AF: 0.342 AC: 1756 AN: 5138

South Asian (SAS) AF: 0.251 AC: 1204 AN: 4794

European-Finnish (FIN) AF: 0.351 AC: 3702 AN: 10542

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21375 AN: 67910

Other (OTH) AF: 0.263 AC: 554 AN: 2108

Alfa AF: 0.307 Hom.: 4187

Bravo AF: 0.249

Asia WGS AF: 0.254 AC: 886 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.88
PhyloP100		-1.9
BranchPoint Hunter		0.0
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: rs13032404; hg19: chr2-238233483; COSMIC: COSV55083654;