rs915786

chr21-46122947-A-Gchr21-46122947-A-Tchr21-46122947-A-C

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.1671+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,611,788 control chromosomes in the GnomAD database, including 542,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56015 hom., cov: 30)
  • Exomes 𝑓: 0.81 (486176 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.35

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=-0.96).
• BP6: Variant 21-46122947-A-G is Benign according to our data. Variant chr21-46122947-A-G is described in ClinVar as [Benign]. Clinvar id is 93914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46122947-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1671+10A>G		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.1671+10A>G		intron_variant		ENST00000397763.6
COL6A2	NM_058175.3	c.1671+10A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1671+10A>G		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1671+10A>G		intron_variant		5	NM_058174.3
COL6A2	ENST00000409416.6	c.1671+10A>G		intron_variant		5
COL6A2	ENST00000413758.1	c.294+10A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129896 AN: 151906 Hom.: 55951 Cov.: 30

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.874

GnomAD3 exomes AF: 0.816 AC: 203912 AN: 249962 Hom.: 84184 AF XY: 0.801 AC XY: 108551 AN XY: 135588

Gnomad AFR exome AF: 0.949

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.870

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.794

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.814 AC: 1188273 AN: 1459764 Hom.: 486176 Cov.: 44 AF XY: 0.807 AC XY: 586222 AN XY: 726236

Gnomad4 AFR exome AF: 0.950

Gnomad4 AMR exome AF: 0.913

Gnomad4 ASJ exome AF: 0.797

Gnomad4 EAS exome AF: 0.913

Gnomad4 SAS exome AF: 0.632

Gnomad4 FIN exome AF: 0.794

Gnomad4 NFE exome AF: 0.818

Gnomad4 OTH exome AF: 0.816

GnomAD4 genome AF: 0.855 AC: 130017 AN: 152024 Hom.: 56015 Cov.: 30 AF XY: 0.851 AC XY: 63210 AN XY: 74272

Gnomad4 AFR AF: 0.947

Gnomad4 AMR AF: 0.891

Gnomad4 ASJ AF: 0.796

Gnomad4 EAS AF: 0.884

Gnomad4 SAS AF: 0.642

Gnomad4 FIN AF: 0.788

Gnomad4 NFE AF: 0.818

Gnomad4 OTH AF: 0.874

Alfa AF: 0.825 Hom.: 11358

Bravo AF: 0.873

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2015	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	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 31, 2012	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Myosclerosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Bethlem myopathy 1A Benign:2

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

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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	-0.96
Cadd	Benign	0.064
Dann	Benign	0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs915786; hg19: chr21-47542861;