rs13032404

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-237324840-G-A
• chr2-237324840-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 95022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237324840-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.9494-26C>T		intron_variant	Intron 43 of 43	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.8876-26C>T		intron_variant	Intron 42 of 42		NP_476508.2
COL6A3	NM_057166.5	c.7673-26C>T		intron_variant	Intron 40 of 40		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.9494-26C>T		intron_variant	Intron 43 of 43	1	NM_004369.4	ENSP00000295550.4

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

GnomAD3 exomes AF: 0.290 AC: 71466 AN: 246308 Hom.: 10837 AF XY: 0.294 AC XY: 39200 AN XY: 133428

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 SAS exome AF: 0.253

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

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.256

Gnomad4 ASJ exome AF: 0.317

Gnomad4 EAS exome AF: 0.389

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.290

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

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.266

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.342

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.263

Alfa AF: 0.303 Hom.: 2674

Bravo AF: 0.249

Asia WGS AF: 0.254 AC: 886 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 02, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 40. Only high quality variants are reported. -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.88
BranchPoint Hunter		0.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs13032404; hg19: chr2-238233483; COSMIC: COSV55083654;