rs762438

chr21-46116632-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):c.928-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 1,612,294 control chromosomes in the GnomAD database, including 205,065 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (17064 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188001 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.87

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46116632-C-T is Benign according to our data. Variant chr21-46116632-C-T is described in ClinVar as [Benign]. Clinvar id is 93963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46116632-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.928-19C>T		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.928-19C>T		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.928-19C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.928-19C>T		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.928-19C>T		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.928-19C>T		intron_variant		5
COL6A2	ENST00000485591.1	n.584-19C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.454 AC: 69055 AN: 151958 Hom.: 17046 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.504 AC: 125989 AN: 249874 Hom.: 33503 AF XY: 0.496 AC XY: 67256 AN XY: 135540

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.657

Gnomad ASJ exome AF: 0.530

Gnomad EAS exome AF: 0.427

Gnomad SAS exome AF: 0.358

Gnomad FIN exome AF: 0.638

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.502 AC: 733123 AN: 1460216 Hom.: 188001 Cov.: 54 AF XY: 0.498 AC XY: 361697 AN XY: 726432

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.648

Gnomad4 ASJ exome AF: 0.531

Gnomad4 EAS exome AF: 0.426

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.627

Gnomad4 NFE exome AF: 0.512

Gnomad4 OTH exome AF: 0.488

GnomAD4 genome AF: 0.454 AC: 69088 AN: 152078 Hom.: 17064 Cov.: 32 AF XY: 0.461 AC XY: 34243 AN XY: 74318

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.531

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.365

Gnomad4 FIN AF: 0.631

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.461

Alfa AF: 0.487 Hom.: 9516

Bravo AF: 0.443

Asia WGS AF: 0.407 AC: 1417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2013	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.26
Dann	Benign	0.37

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: rs762438; hg19: chr21-47536546; COSMIC: COSV56002304; COSMIC: COSV56002304;