21-46119876-A-G

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.1332+26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,550,732 control chromosomes in the GnomAD database, including 523,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51101 hom., cov: 32)
  • Exomes 𝑓: 0.82 (472263 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.972

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=-0.94).
• BP6: Variant 21-46119876-A-G is Benign according to our data. Variant chr21-46119876-A-G is described in ClinVar as [Benign]. Clinvar id is 93905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46119876-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1332+26A>G		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1332+26A>G		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1332+26A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1332+26A>G		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1332+26A>G		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1332+26A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.819 AC: 124382 AN: 151894 Hom.: 51040 Cov.: 32

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.844

Gnomad AMR AF: 0.879

Gnomad ASJ AF: 0.792

Gnomad EAS AF: 0.887

Gnomad SAS AF: 0.671

Gnomad FIN AF: 0.798

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.842

GnomAD3 exomes AF: 0.811 AC: 128153 AN: 158014 Hom.: 52448 AF XY: 0.799 AC XY: 66718 AN XY: 83526

Gnomad AFR exome AF: 0.798

Gnomad AMR exome AF: 0.904

Gnomad ASJ exome AF: 0.783

Gnomad EAS exome AF: 0.867

Gnomad SAS exome AF: 0.663

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.823

Gnomad OTH exome AF: 0.827

GnomAD4 exome AF: 0.820 AC: 1147313 AN: 1398720 Hom.: 472263 Cov.: 35 AF XY: 0.815 AC XY: 562459 AN XY: 690130

Gnomad4 AFR exome AF: 0.793

Gnomad4 AMR exome AF: 0.904

Gnomad4 ASJ exome AF: 0.796

Gnomad4 EAS exome AF: 0.916

Gnomad4 SAS exome AF: 0.661

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.828

Gnomad4 OTH exome AF: 0.816

GnomAD4 genome AF: 0.819 AC: 124500 AN: 152012 Hom.: 51101 Cov.: 32 AF XY: 0.817 AC XY: 60723 AN XY: 74294

Gnomad4 AFR AF: 0.799

Gnomad4 AMR AF: 0.880

Gnomad4 ASJ AF: 0.792

Gnomad4 EAS AF: 0.888

Gnomad4 SAS AF: 0.670

Gnomad4 FIN AF: 0.798

Gnomad4 NFE AF: 0.827

Gnomad4 OTH AF: 0.842

Alfa AF: 0.816 Hom.: 9432

Bravo AF: 0.828

Asia WGS AF: 0.800 AC: 2782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	-	- -

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

- -

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.063
Dann	Benign	0.34

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: rs3737362; hg19: chr21-47539790; COSMIC: COSV56012319; COSMIC: COSV56012319;