rs78822624

Positions:

• chr21-46112586-C-T

Variant summary

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

The NM_001849.4(COL6A2):​c.714+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 1,611,360 control chromosomes in the GnomAD database, including 2,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (133 hom., cov: 32)
  • Exomes 𝑓: 0.048 (1895 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.558

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 21-46112586-C-T is Benign according to our data. Variant chr21-46112586-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46112586-C-T is described in Lovd as [Benign]. Variant chr21-46112586-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.714+9C>T		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.714+9C>T		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.714+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.714+9C>T		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.714+9C>T		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.714+9C>T		intron_variant		5
COL6A2	ENST00000460886.1	n.160+9C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5330 AN: 151990 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0540

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0530

Gnomad OTH AF: 0.0273

GnomAD3 exomes AF: 0.0384 AC: 9347 AN: 243458 Hom.: 235 AF XY: 0.0400 AC XY: 5336 AN XY: 133256

Gnomad AFR exome AF: 0.00927

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000219

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.0715

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0481 AC: 70154 AN: 1459252 Hom.: 1895 Cov.: 34 AF XY: 0.0477 AC XY: 34645 AN XY: 725936

Gnomad4 AFR exome AF: 0.00882

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.0715

Gnomad4 NFE exome AF: 0.0533

Gnomad4 OTH exome AF: 0.0401

GnomAD4 genome AF: 0.0350 AC: 5327 AN: 152108 Hom.: 133 Cov.: 32 AF XY: 0.0351 AC XY: 2610 AN XY: 74380

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.000974

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0623

Gnomad4 NFE AF: 0.0530

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0477 Hom.: 65

Bravo AF: 0.0300

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 15, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.7
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78822624; hg19: chr21-47532500;