rs61735830

chr21-46126035-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001849.4(COL6A2):c.2220T>C(p.Asp740=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00308 in 1,612,996 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (8 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.63

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 21-46126035-T-C is Benign according to our data. Variant chr21-46126035-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 166933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.63 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2220T>C	p.Asp740=	synonymous_variant	26/28	ENST00000300527.9
COL6A2	NM_058174.3	c.2220T>C	p.Asp740=	synonymous_variant	26/28	ENST00000397763.6
COL6A2	NM_058175.3	c.2220T>C	p.Asp740=	synonymous_variant	26/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2220T>C	p.Asp740=	synonymous_variant	26/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.2220T>C	p.Asp740=	synonymous_variant	26/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.2220T>C	p.Asp740=	synonymous_variant	25/27	5

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00252 AC: 632 AN: 250998 Hom.: 1 AF XY: 0.00245 AC XY: 333 AN XY: 135800

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00495

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00315 AC: 4605 AN: 1460716 Hom.: 8 Cov.: 38 AF XY: 0.00299 AC XY: 2175 AN XY: 726660

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.00512

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74462

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00302 Hom.: 2

Bravo AF: 0.00206

EpiCase AF: 0.00382

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	COL6A2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2020	- -

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

Invitae

Jan 28, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	0.10
Dann	Benign	0.64

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: rs61735830; hg19: chr21-47545949;