21-46131919-C-T

Position:

• chr21-46131919-C-T

Variant summary

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

The ENST00000300527.9(COL6A2):​c.2462-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,547,548 control chromosomes in the GnomAD database, including 240,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22538 hom., cov: 34)
  • Exomes 𝑓: 0.56 (218195 hom.)
• Consequence: COL6A2 ENST00000300527.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.42

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=-0.78).
• BP6: Variant 21-46131919-C-T is Benign according to our data. Variant chr21-46131919-C-T is described in ClinVar as [Benign]. Clinvar id is 93940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46131919-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2462-35C>T		intron_variant		ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2462-35C>T		intron_variant		1	NM_001849.4	ENSP00000300527	P1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81616 AN: 151976 Hom.: 22513 Cov.: 34

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.550

GnomAD3 exomes AF: 0.553 AC: 86242 AN: 155946 Hom.: 24812 AF XY: 0.536 AC XY: 45718 AN XY: 85294

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.495

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.582

GnomAD4 exome AF: 0.555 AC: 774969 AN: 1395454 Hom.: 218195 Cov.: 30 AF XY: 0.549 AC XY: 379567 AN XY: 690778

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.713

Gnomad4 ASJ exome AF: 0.575

Gnomad4 EAS exome AF: 0.466

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.639

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.546

GnomAD4 genome AF: 0.537 AC: 81687 AN: 152094 Hom.: 22538 Cov.: 34 AF XY: 0.539 AC XY: 40094 AN XY: 74352

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.577

Gnomad4 EAS AF: 0.501

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.638

Gnomad4 NFE AF: 0.574

Gnomad4 OTH AF: 0.545

Alfa AF: 0.558 Hom.: 4380

Bravo AF: 0.539

Asia WGS AF: 0.453 AC: 1573 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Bethlem myopathy 1A 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	-0.78
CADD	Benign	0.56
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs7279622; hg19: chr21-47551833; COSMIC: COSV52426489; COSMIC: COSV52426489;