chr21-46125975-C-G

Position:

• chr21-46125975-C-G

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.2160C>G​(p.Arg720Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,613,124 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (97 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.111

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=-0.55).
• BP6: Variant 21-46125975-C-G is Benign according to our data. Variant chr21-46125975-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 93934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125975-C-G is described in Lovd as [Benign]. Variant chr21-46125975-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2160C>G	p.Arg720Arg	synonymous_variant	26/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2160C>G	p.Arg720Arg	synonymous_variant	26/28		NP_478054.2
COL6A2	NM_058175.3	c.2160C>G	p.Arg720Arg	synonymous_variant	26/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2160C>G	p.Arg720Arg	synonymous_variant	26/28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2160C>G	p.Arg720Arg	synonymous_variant	26/28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2160C>G	p.Arg720Arg	synonymous_variant	25/27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0174 AC: 2648 AN: 152140 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.0595

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00432 AC: 1084 AN: 251076 Hom.: 33 AF XY: 0.00313 AC XY: 425 AN XY: 135838

Gnomad AFR exome AF: 0.0597

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00185 AC: 2704 AN: 1460866 Hom.: 97 Cov.: 79 AF XY: 0.00163 AC XY: 1185 AN XY: 726726

Gnomad4 AFR exome AF: 0.0672

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0174 AC: 2654 AN: 152258 Hom.: 65 Cov.: 33 AF XY: 0.0167 AC XY: 1246 AN XY: 74438

Gnomad4 AFR AF: 0.0595

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00519 Hom.: 6

Bravo AF: 0.0200

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 18, 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	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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

- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.5
DANN	Benign	0.61

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: rs61735829; hg19: chr21-47545889;