rs17357592

Positions:

• chr21-46122865-C-T

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.1609-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,276 control chromosomes in the GnomAD database, including 24,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1363 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22827 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Scores: Splicing: ADA: 0.00001742
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.833

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=-0.86).
• BP6: Variant 21-46122865-C-T is Benign according to our data. Variant chr21-46122865-C-T is described in ClinVar as [Benign]. Clinvar id is 93913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46122865-C-T 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	Protein	UniProt
COL6A2	NM_001849.4	c.1609-10C>T		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1609-10C>T		intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1609-10C>T		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1609-10C>T		intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1609-10C>T		intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1609-10C>T		intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.232-10C>T		intron_variant		3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17889 AN: 152088 Hom.: 1365 Cov.: 32

Gnomad AFR AF: 0.0494

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0193

Gnomad SAS AF: 0.0752

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.121 AC: 30183 AN: 250224 Hom.: 2292 AF XY: 0.124 AC XY: 16855 AN XY: 135692

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0246

Gnomad SAS exome AF: 0.0784

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.167 AC: 243740 AN: 1459070 Hom.: 22827 Cov.: 33 AF XY: 0.165 AC XY: 119433 AN XY: 725920

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.0731

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0778

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.156

GnomAD4 genome AF: 0.118 AC: 17891 AN: 152206 Hom.: 1363 Cov.: 32 AF XY: 0.111 AC XY: 8259 AN XY: 74424

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.0932

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.128

Alfa AF: 0.168 Hom.: 3979

Bravo AF: 0.118

Asia WGS AF: 0.0640 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 19, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2016	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Myosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.0
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs17357592; hg19: chr21-47542779;