rs6725567

chr2-237344875-C-T

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.7175-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0277 in 1,613,880 control chromosomes in the GnomAD database, including 1,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (791 hom., cov: 32)
  • Exomes 𝑓: 0.024 (1052 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.186

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: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-237344875-C-T is Benign according to our data. Variant chr2-237344875-C-T is described in ClinVar as [Benign]. Clinvar id is 94982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237344875-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.7175-32G>A		intron_variant		ENST00000295550.9
COL6A3	NM_057166.5	c.5354-32G>A		intron_variant
COL6A3	NM_057167.4	c.6557-32G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.7175-32G>A		intron_variant		1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.5354-32G>A		intron_variant		1
COL6A3	ENST00000353578.9	c.6557-32G>A		intron_variant		5
COL6A3	ENST00000491769.1	n.1429-32G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10246 AN: 152114 Hom.: 790 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0330 AC: 8259 AN: 250182 Hom.: 396 AF XY: 0.0302 AC XY: 4089 AN XY: 135368

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.0422

Gnomad EAS exome AF: 0.00408

Gnomad SAS exome AF: 0.0267

Gnomad FIN exome AF: 0.00762

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0303

GnomAD4 exome AF: 0.0235 AC: 34378 AN: 1461648 Hom.: 1052 Cov.: 34 AF XY: 0.0231 AC XY: 16817 AN XY: 727142

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0270

Gnomad4 ASJ exome AF: 0.0429

Gnomad4 EAS exome AF: 0.00181

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.00929

Gnomad4 NFE exome AF: 0.0181

Gnomad4 OTH exome AF: 0.0338

GnomAD4 genome AF: 0.0674 AC: 10264 AN: 152232 Hom.: 791 Cov.: 32 AF XY: 0.0649 AC XY: 4830 AN XY: 74440

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.0412

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0634

Alfa AF: 0.0500 Hom.: 112

Bravo AF: 0.0758

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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	-0.82
Cadd	Benign	4.1
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6725567; hg19: chr2-238253518;