rs9981981

Positions:

• chr21-46124924-G-A

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.1770+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 1,612,788 control chromosomes in the GnomAD database, including 5,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (612 hom., cov: 32)
  • Exomes 𝑓: 0.051 (5060 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001405
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.935

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=-0.49).
• BP6: Variant 21-46124924-G-A is Benign according to our data. Variant chr21-46124924-G-A is described in ClinVar as [Benign]. Clinvar id is 93921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124924-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1770+4G>A		splice_region_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1770+4G>A		splice_region_variant, intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1770+4G>A		splice_region_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1770+4G>A		splice_region_variant, intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1770+4G>A		splice_region_variant, intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1770+4G>A		splice_region_variant, intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.393+4G>A		splice_region_variant, intron_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.0661 AC: 10052 AN: 152172 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.0856

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0755

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.0920

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0360

Gnomad OTH AF: 0.0821

GnomAD3 exomes AF: 0.0751 AC: 18797 AN: 250168 Hom.: 1580 AF XY: 0.0722 AC XY: 9792 AN XY: 135652

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.0895

Gnomad ASJ exome AF: 0.0349

Gnomad EAS exome AF: 0.339

Gnomad SAS exome AF: 0.0819

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0378

Gnomad OTH exome AF: 0.0578

GnomAD4 exome AF: 0.0506 AC: 73919 AN: 1460498 Hom.: 5060 Cov.: 34 AF XY: 0.0514 AC XY: 37325 AN XY: 726546

Gnomad4 AFR exome AF: 0.0856

Gnomad4 AMR exome AF: 0.0894

Gnomad4 ASJ exome AF: 0.0369

Gnomad4 EAS exome AF: 0.409

Gnomad4 SAS exome AF: 0.0790

Gnomad4 FIN exome AF: 0.0252

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0592

GnomAD4 genome AF: 0.0660 AC: 10053 AN: 152290 Hom.: 612 Cov.: 32 AF XY: 0.0679 AC XY: 5056 AN XY: 74460

Gnomad4 AFR AF: 0.0853

Gnomad4 AMR AF: 0.0754

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.347

Gnomad4 SAS AF: 0.0921

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.0360

Gnomad4 OTH AF: 0.0836

Alfa AF: 0.0446 Hom.: 285

Bravo AF: 0.0730

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0390

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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)	May 07, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 06, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myosclerosis Benign:1

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

Feb 01, 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	-0.49
CADD	Benign	18
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.11		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: rs9981981; hg19: chr21-47544838; COSMIC: COSV56006103;