rs1077182

Positions:

• chr21-46121639-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.1521+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,611,126 control chromosomes in the GnomAD database, including 24,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1376 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22931 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.648

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=-0.87).
• BP6: Variant 21-46121639-A-G is Benign according to our data. Variant chr21-46121639-A-G is described in ClinVar as [Benign]. Clinvar id is 93908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46121639-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1521+21A>G		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1521+21A>G		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1521+21A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1521+21A>G		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1521+21A>G		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1521+21A>G		intron_variant		5
COL6A2	ENST00000413758.1	c.144+21A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17937 AN: 152088 Hom.: 1377 Cov.: 33

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.120 AC: 29797 AN: 247474 Hom.: 2231 AF XY: 0.124 AC XY: 16678 AN XY: 134562

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0245

Gnomad SAS exome AF: 0.0783

Gnomad FIN exome AF: 0.0625

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.168 AC: 244629 AN: 1458920 Hom.: 22931 Cov.: 33 AF XY: 0.165 AC XY: 119876 AN XY: 725834

Gnomad4 AFR exome AF: 0.0432

Gnomad4 AMR exome AF: 0.0731

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.0777

Gnomad4 FIN exome AF: 0.0680

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.118 AC: 17941 AN: 152206 Hom.: 1376 Cov.: 33 AF XY: 0.111 AC XY: 8269 AN XY: 74396

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.0198

Gnomad4 SAS AF: 0.0737

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.183

Gnomad4 OTH AF: 0.129

Alfa AF: 0.152 Hom.: 376

Bravo AF: 0.118

Asia WGS AF: 0.0650 AC: 228 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 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	-0.87
CADD	Benign	4.5
DANN	Benign	0.56

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: rs1077182; hg19: chr21-47541553;