rs9977394

Positions:

• chr21-46132216-A-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.2724A>G​(p.Thr908Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,592,298 control chromosomes in the GnomAD database, including 10,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1871 hom., cov: 34)
  • Exomes 𝑓: 0.10 (8978 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.0370

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=-0.93).
• BP6: Variant 21-46132216-A-G is Benign according to our data. Variant chr21-46132216-A-G is described in ClinVar as [Benign]. Clinvar id is 93945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46132216-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.254 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2724A>G	p.Thr908Thr	synonymous_variant	28/28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2724A>G	p.Thr908Thr	synonymous_variant	28/28	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20795 AN: 152062 Hom.: 1868 Cov.: 34

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0882

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.0371

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.128

GnomAD3 exomes AF: 0.0984 AC: 20809 AN: 211458 Hom.: 1406 AF XY: 0.102 AC XY: 11820 AN XY: 115718

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.0521

Gnomad ASJ exome AF: 0.0871

Gnomad EAS exome AF: 0.0247

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0888

GnomAD4 exome AF: 0.104 AC: 149607 AN: 1440118 Hom.: 8978 Cov.: 35 AF XY: 0.105 AC XY: 75356 AN XY: 715164

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.0560

Gnomad4 ASJ exome AF: 0.0901

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.169

Gnomad4 FIN exome AF: 0.0389

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.137 AC: 20844 AN: 152180 Hom.: 1871 Cov.: 34 AF XY: 0.133 AC XY: 9881 AN XY: 74414

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.0800

Gnomad4 ASJ AF: 0.0882

Gnomad4 EAS AF: 0.0255

Gnomad4 SAS AF: 0.182

Gnomad4 FIN AF: 0.0371

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.132

Alfa AF: 0.109 Hom.: 383

Bravo AF: 0.144

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Glutamate formiminotransferase deficiency Benign:1

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Collagen 6-related myopathy Benign:1

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	-0.93
CADD	Benign	0.27
DANN	Benign	0.28

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: rs9977394; hg19: chr21-47552130;