rs113002150

chr21-46132009-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001849.4(COL6A2):c.2517C>T(p.Asp839=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,609,770 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.07

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 21-46132009-C-T is Benign according to our data. Variant chr21-46132009-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196113.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=4}. Variant chr21-46132009-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.07 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2517C>T	p.Asp839=	synonymous_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2517C>T	p.Asp839=	synonymous_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152210 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000363 AC: 87 AN: 239484 Hom.: 0 AF XY: 0.000388 AC XY: 51 AN XY: 131398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000876

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000625

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000438

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.000432 AC: 629 AN: 1457560 Hom.: 2 Cov.: 33 AF XY: 0.000462 AC XY: 335 AN XY: 725298

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000958

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000731

Gnomad4 FIN exome AF: 0.000159

Gnomad4 NFE exome AF: 0.000444

Gnomad4 OTH exome AF: 0.000349

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152210 Hom.: 1 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74358

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000558 Hom.: 0

Bravo AF: 0.000412

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000475

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	- -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 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. -

COL6A2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.5
Dann	Benign	0.93

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: rs113002150; hg19: chr21-47551923;