rs8132521

Positions:

chr21-46001950-C-T

Variant summary

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

The NM_001848.3(COL6A1):c.1957-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,609,230 control chromosomes in the GnomAD database, including 80,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.29 ( 7478 hom., cov: 33)

Exomes 𝑓: 0.30 ( 72705 hom. )

Consequence

COL6A1
NM_001848.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00001753

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0250

Variant links:

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 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=-0.85).

BP6

Variant 21-46001950-C-T is Benign according to our data. Variant chr21-46001950-C-T is described in ClinVar as [Benign]. Clinvar id is 93842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46001950-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.1957-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.1957-11C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes

AF:

0.295

AC:

44817

AN:

151902

Hom.:

7467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.184

Gnomad AMI

AF:

0.402

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.368

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.394

Gnomad FIN

AF:

0.358

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.313

GnomAD3 exomes

AF:

0.364

AC:

86718

AN:

238236

Hom.:

17481

AF XY:

0.359

AC XY:

46562

AN XY:

129638

show subpopulations

Gnomad AFR exome

AF:

0.185

Gnomad AMR exome

AF:

0.514

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.637

Gnomad SAS exome

AF:

0.378

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.293

Gnomad OTH exome

AF:

0.366

GnomAD4 exome

AF:

0.305

AC:

444424

AN:

1457210

Hom.:

72705

Cov.:

AF XY:

0.307

AC XY:

222831

AN XY:

724804

show subpopulations

Gnomad4 AFR exome

AF:

0.173

Gnomad4 AMR exome

AF:

0.504

Gnomad4 ASJ exome

AF:

0.365

Gnomad4 EAS exome

AF:

0.622

Gnomad4 SAS exome

AF:

0.377

Gnomad4 FIN exome

AF:

0.358

Gnomad4 NFE exome

AF:

0.279

Gnomad4 OTH exome

AF:

0.324

GnomAD4 genome

AF:

0.295

AC:

44843

AN:

152020

Hom.:

7478

Cov.:

AF XY:

0.302

AC XY:

22464

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.184

Gnomad4 AMR

AF:

0.409

Gnomad4 ASJ

AF:

0.368

Gnomad4 EAS

AF:

0.637

Gnomad4 SAS

AF:

0.393

Gnomad4 FIN

AF:

0.358

Gnomad4 NFE

AF:

0.288

Gnomad4 OTH

AF:

0.317

Alfa

AF:

0.306

Hom.:

1411

Bravo

AF:

0.294

Asia WGS

AF:

0.496

AC:

1723

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

Bethlem myopathy 1A

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.0

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

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

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