rs73159701

Positions:

chr21-46120507-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001849.4(COL6A2):c.1333-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,512,874 control chromosomes in the GnomAD database, including 37,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2760 hom., cov: 34)

Exomes 𝑓: 0.22 ( 34441 hom. )

Consequence

COL6A2
NM_001849.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001797

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.804

Variant links:

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]

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 21-46120507-T-C is Benign according to our data. Variant chr21-46120507-T-C is described in ClinVar as [Benign]. Clinvar id is 93906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46120507-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
COL6A2	NM_001849.4 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_001849.4	ENSP00000300527	P1	P12110-1
COL6A2	ENST00000397763.6 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5	NM_058174.3	ENSP00000380870		P12110-2
COL6A2	ENST00000409416.6 linkuse as main transcript	c.1333-8T>C	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5		ENSP00000387115		P12110-3

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27138

AN:

151980

Hom.:

2759

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.169

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.307

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.0754

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.213

GnomAD3 exomes

AF:

0.179

AC:

20432

AN:

114234

Hom.:

2088

AF XY:

0.181

AC XY:

11094

AN XY:

61272

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.155

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.291

Gnomad SAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.0747

Gnomad NFE exome

AF:

0.219

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.217

AC:

295954

AN:

1360774

Hom.:

34441

Cov.:

AF XY:

0.216

AC XY:

144602

AN XY:

670540

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.154

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.385

Gnomad4 SAS exome

AF:

0.151

Gnomad4 FIN exome

AF:

0.0821

Gnomad4 NFE exome

AF:

0.228

Gnomad4 OTH exome

AF:

0.213

GnomAD4 genome

AF:

0.178

AC:

27144

AN:

152100

Hom.:

2760

Cov.:

AF XY:

0.173

AC XY:

12849

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.169

Gnomad4 ASJ

AF:

0.186

Gnomad4 EAS

AF:

0.307

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.0754

Gnomad4 NFE

AF:

0.220

Gnomad4 OTH

AF:

0.213

Alfa

AF:

0.189

Hom.:

952

Bravo

AF:

0.185

Asia WGS

AF:

0.220

AC:

767

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 07, 2016	- -
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	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2016	- -

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

Feb 01, 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

-0.75

CADD

Benign

3.4

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.016

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over