rs2839114

Positions:

• chr21-46125999-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001849.4(COL6A2):​c.2184G>A​(p.Val728=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,612,720 control chromosomes in the GnomAD database, including 112,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9456 hom., cov: 32)
  • Exomes 𝑓: 0.37 (103082 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.86

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 21-46125999-G-A is Benign according to our data. Variant chr21-46125999-G-A is described in ClinVar as [Benign]. Clinvar id is 93936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125999-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2184G>A	p.Val728=	synonymous_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2184G>A	p.Val728=	synonymous_variant	26/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.2184G>A	p.Val728=	synonymous_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2184G>A	p.Val728=	synonymous_variant	26/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.2184G>A	p.Val728=	synonymous_variant	26/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.2184G>A	p.Val728=	synonymous_variant	25/27	5		ENSP00000387115

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49959 AN: 151914 Hom.: 9442 Cov.: 32

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.389 AC: 97680 AN: 250960 Hom.: 20865 AF XY: 0.380 AC XY: 51596 AN XY: 135766

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.434

Gnomad SAS exome AF: 0.278

Gnomad FIN exome AF: 0.466

Gnomad NFE exome AF: 0.373

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.369 AC: 539562 AN: 1460686 Hom.: 103082 Cov.: 75 AF XY: 0.367 AC XY: 266375 AN XY: 726608

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.329 AC: 49979 AN: 152034 Hom.: 9456 Cov.: 32 AF XY: 0.335 AC XY: 24906 AN XY: 74300

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.488

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.445

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.341

Alfa AF: 0.348 Hom.: 4986

Bravo AF: 0.324

Asia WGS AF: 0.365 AC: 1268 AN: 3478

EpiCase AF: 0.361

EpiControl AF: 0.358

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 16, 2017	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	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	Eurofins Ntd Llc (ga)	Jun 28, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Myosclerosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 13, 2017	- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.7
DANN	Benign	0.69

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: rs2839114; hg19: chr21-47545913; COSMIC: COSV56000335; COSMIC: COSV56000335;