2-237324767-C-G

Position:

• chr2-237324767-C-G

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.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,613,246 control chromosomes in the GnomAD database, including 12,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2041 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10410 hom.)
• Consequence: COL6A3 NM_004369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.09

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=-0.81).
• BP6: Variant 2-237324767-C-G is Benign according to our data. Variant chr2-237324767-C-G is described in ClinVar as [Benign]. Clinvar id is 94900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237324767-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.*7G>C		3_prime_UTR_variant	44/44	ENST00000295550.9
COL6A3	NM_057166.5	c.*7G>C		3_prime_UTR_variant	41/41
COL6A3	NM_057167.4	c.*7G>C		3_prime_UTR_variant	43/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.*7G>C		3_prime_UTR_variant	44/44	1	NM_004369.4	P1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22461 AN: 151924 Hom.: 2033 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.0955

Gnomad OTH AF: 0.154

GnomAD3 exomes AF: 0.145 AC: 36031 AN: 249246 Hom.: 3201 AF XY: 0.140 AC XY: 18890 AN XY: 134896

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.162

Gnomad EAS exome AF: 0.232

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.0785

Gnomad NFE exome AF: 0.0961

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.109 AC: 159599 AN: 1461202 Hom.: 10410 Cov.: 31 AF XY: 0.111 AC XY: 80397 AN XY: 726914

Gnomad4 AFR exome AF: 0.234

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.202

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.0754

Gnomad4 NFE exome AF: 0.0913

Gnomad4 OTH exome AF: 0.131

GnomAD4 genome AF: 0.148 AC: 22493 AN: 152044 Hom.: 2041 Cov.: 32 AF XY: 0.148 AC XY: 10976 AN XY: 74306

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.170

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.199

Gnomad4 FIN AF: 0.0801

Gnomad4 NFE AF: 0.0955

Gnomad4 OTH AF: 0.154

Alfa AF: 0.0783 Hom.: 121

Bravo AF: 0.156

Asia WGS AF: 0.246 AC: 855 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2016	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 28% 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: 26. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.71

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: rs4663722; hg19: chr2-238233410;