rs73382466

Positions:

• chr21-46124855-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.1735-30A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0891 in 1,612,104 control chromosomes in the GnomAD database, including 6,722 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (585 hom., cov: 33)
  • Exomes 𝑓: 0.089 (6137 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.358

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=-0.92).
• BP6: Variant 21-46124855-A-G is Benign according to our data. Variant chr21-46124855-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 93919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124855-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1735-30A>G		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1735-30A>G		intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1735-30A>G		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1735-30A>G		intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1735-30A>G		intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1735-30A>G		intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.358-30A>G		intron_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.0897 AC: 13645 AN: 152086 Hom.: 584 Cov.: 33

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0789

Gnomad EAS AF: 0.0559

Gnomad SAS AF: 0.0524

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0889

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0825 AC: 20628 AN: 250142 Hom.: 911 AF XY: 0.0821 AC XY: 11131 AN XY: 135602

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0765

Gnomad ASJ exome AF: 0.0776

Gnomad EAS exome AF: 0.0600

Gnomad SAS exome AF: 0.0627

Gnomad FIN exome AF: 0.0828

Gnomad NFE exome AF: 0.0909

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0891 AC: 130046 AN: 1459900 Hom.: 6137 Cov.: 35 AF XY: 0.0884 AC XY: 64203 AN XY: 726268

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0782

Gnomad4 ASJ exome AF: 0.0790

Gnomad4 EAS exome AF: 0.0433

Gnomad4 SAS exome AF: 0.0627

Gnomad4 FIN exome AF: 0.0860

Gnomad4 NFE exome AF: 0.0931

Gnomad4 OTH exome AF: 0.0865

GnomAD4 genome AF: 0.0898 AC: 13661 AN: 152204 Hom.: 585 Cov.: 33 AF XY: 0.0886 AC XY: 6594 AN XY: 74440

Gnomad4 AFR AF: 0.0999

Gnomad4 AMR AF: 0.0937

Gnomad4 ASJ AF: 0.0789

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.0889

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0866 Hom.: 110

Bravo AF: 0.0926

Asia WGS AF: 0.0600 AC: 210 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely 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:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	-0.92
CADD	Benign	0.098
DANN	Benign	0.19

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: rs73382466; hg19: chr21-47544769; COSMIC: COSV56006064;