2-237346477-C-T

Position:

• chr2-237346477-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000295550.9(COL6A3):​c.7092+26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,606,726 control chromosomes in the GnomAD database, including 17,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3481 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13709 hom.)
• Consequence: COL6A3 ENST00000295550.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0190

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-237346477-C-T is Benign according to our data. Variant chr2-237346477-C-T is described in ClinVar as [Benign]. Clinvar id is 94979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237346477-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7092+26G>A		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6474+26G>A		intron_variant			NP_476508.2
COL6A3	NM_057166.5	c.5271+26G>A		intron_variant			NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7092+26G>A		intron_variant		1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5271+26G>A		intron_variant		1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6474+26G>A		intron_variant		5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1346+26G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28625 AN: 151922 Hom.: 3475 Cov.: 32

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.0868

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.0526

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.193

GnomAD3 exomes AF: 0.150 AC: 37751 AN: 251186 Hom.: 3378 AF XY: 0.146 AC XY: 19823 AN XY: 135812

Gnomad AFR exome AF: 0.346

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.0512

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.130 AC: 188405 AN: 1454686 Hom.: 13709 Cov.: 30 AF XY: 0.129 AC XY: 93627 AN XY: 724072

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.0536

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.189 AC: 28664 AN: 152040 Hom.: 3481 Cov.: 32 AF XY: 0.188 AC XY: 13958 AN XY: 74330

Gnomad4 AFR AF: 0.334

Gnomad4 AMR AF: 0.207

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.0524

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.191

Alfa AF: 0.162 Hom.: 550

Bravo AF: 0.201

Asia WGS AF: 0.112 AC: 392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 35% 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: 33. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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. -

Dystonia 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.4
DANN	Benign	0.46

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: rs2270656; hg19: chr2-238255120;