rs2646263

Positions:

• chr2-237348710-A-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.6880-47T>C 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 1,555,482 control chromosomes in the GnomAD database, including 15,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2658 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13013 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.72

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=-0.92).
• BP6: Variant 2-237348710-A-G is Benign according to our data. Variant chr2-237348710-A-G is described in ClinVar as [Benign]. Clinvar id is 94972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237348710-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6880-47T>C		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6262-47T>C		intron_variant			NP_476508.2
COL6A3	NM_057166.5	c.5059-47T>C		intron_variant			NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6880-47T>C		intron_variant		1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5059-47T>C		intron_variant		1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6262-47T>C		intron_variant		5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1134-47T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26193 AN: 152024 Hom.: 2660 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.147 AC: 36276 AN: 246214 Hom.: 2941 AF XY: 0.144 AC XY: 19204 AN XY: 133000

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0512

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 184359 AN: 1403340 Hom.: 13013 Cov.: 23 AF XY: 0.131 AC XY: 92037 AN XY: 701248

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.0541

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.172 AC: 26210 AN: 152142 Hom.: 2658 Cov.: 32 AF XY: 0.172 AC XY: 12812 AN XY: 74360

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.0526

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.179

Alfa AF: 0.160 Hom.: 648

Bravo AF: 0.182

Asia WGS AF: 0.104 AC: 363 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	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 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	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -

not provided Benign:2

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. -
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	-0.92
CADD	Benign	0.0020
DANN	Benign	0.12

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: rs2646263; hg19: chr2-238257353;