rs2646264

Positions:

• chr2-237348570-C-G
• chr2-237348570-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.6930+43G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,593,010 control chromosomes in the GnomAD database, including 9,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (934 hom., cov: 32)
  • Exomes 𝑓: 0.11 (8496 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.520

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 2-237348570-C-G is Benign according to our data. Variant chr2-237348570-C-G is described in ClinVar as [Benign]. Clinvar id is 94974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237348570-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6930+43G>C		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057166.5	c.5109+43G>C		intron_variant			NP_476507.3
COL6A3	NM_057167.4	c.6312+43G>C		intron_variant			NP_476508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6930+43G>C		intron_variant		1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.5109+43G>C		intron_variant		1		ENSP00000418285
COL6A3	ENST00000353578.9	c.6312+43G>C		intron_variant		5		ENSP00000315873
COL6A3	ENST00000491769.1	n.1184+43G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16475 AN: 152148 Hom.: 934 Cov.: 32

Gnomad AFR AF: 0.0951

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0489

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.115 AC: 27945 AN: 243366 Hom.: 1661 AF XY: 0.114 AC XY: 15019 AN XY: 131340

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.0471

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.107 AC: 153857 AN: 1440744 Hom.: 8496 Cov.: 29 AF XY: 0.107 AC XY: 76852 AN XY: 717192

Gnomad4 AFR exome AF: 0.0960

Gnomad4 AMR exome AF: 0.172

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0523

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.108 AC: 16482 AN: 152266 Hom.: 934 Cov.: 32 AF XY: 0.111 AC XY: 8253 AN XY: 74446

Gnomad4 AFR AF: 0.0950

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.0488

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0631 Hom.: 94

Bravo AF: 0.110

Asia WGS AF: 0.0800 AC: 281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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 38% 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: 35. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
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	7.8
DANN	Benign	0.69

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: rs2646264; hg19: chr2-238257213;