21-46132189-G-T

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.2697G>T(p.Thr899=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,575,690 control chromosomes in the GnomAD database, including 1,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T899T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (89 hom., cov: 34)
  • Exomes 𝑓: 0.042 (1408 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -4.97

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=-0.9).
• BP6: Variant 21-46132189-G-T is Benign according to our data. Variant chr21-46132189-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 93944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46132189-G-T is described in Lovd as [Benign]. Variant chr21-46132189-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.97 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.2697G>T	p.Thr899=	synonymous_variant	28/28	ENST00000300527.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.2697G>T	p.Thr899=	synonymous_variant	28/28	1	NM_001849.4	P1

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4292 AN: 152182 Hom.: 89 Cov.: 34

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0427

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.0342 AC: 6339 AN: 185290 Hom.: 140 AF XY: 0.0367 AC XY: 3696 AN XY: 100766

Gnomad AFR exome AF: 0.00635

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000230

Gnomad SAS exome AF: 0.0537

Gnomad FIN exome AF: 0.0268

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0360

GnomAD4 exome AF: 0.0421 AC: 59891 AN: 1423390 Hom.: 1408 Cov.: 34 AF XY: 0.0424 AC XY: 29916 AN XY: 705294

Gnomad4 AFR exome AF: 0.00657

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0311

Gnomad4 EAS exome AF: 0.0000539

Gnomad4 SAS exome AF: 0.0548

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0455

Gnomad4 OTH exome AF: 0.0373

GnomAD4 genome AF: 0.0281 AC: 4287 AN: 152300 Hom.: 89 Cov.: 34 AF XY: 0.0275 AC XY: 2046 AN XY: 74468

Gnomad4 AFR AF: 0.00753

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0446

Gnomad4 FIN AF: 0.0263

Gnomad4 NFE AF: 0.0427

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0170 Hom.: 13

Bravo AF: 0.0266

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 16, 2012	- -
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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Myosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Glutamate formiminotransferase deficiency 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 31, 2024

- -

Collagen 6-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.094
Dann	Benign	0.88

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: rs11554669; hg19: chr21-47552103; COSMIC: COSV99039003; COSMIC: COSV99039003;