21-46002725-A-G

Position:

chr21-46002725-A-G

Variant summary

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

The NM_001848.3(COL6A1):c.2434+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.861 in 1,552,926 control chromosomes in the GnomAD database, including 576,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.87 ( 57027 hom., cov: 35)

Exomes 𝑓: 0.86 ( 519854 hom. )

Consequence

COL6A1
NM_001848.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.117

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:

COL6A1 (HGNC:):

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=-0.84).

BP6

Variant 21-46002725-A-G is Benign according to our data. Variant chr21-46002725-A-G is described in ClinVar as [Benign]. Clinvar id is 93854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46002725-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2434+15A>G		intron_variant		ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.2434+15A>G		intron_variant		1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.873

AC:

130364

AN:

149364

Hom.:

56967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.908

Gnomad AMI

AF:

0.823

Gnomad AMR

AF:

0.901

Gnomad ASJ

AF:

0.805

Gnomad EAS

AF:

0.868

Gnomad SAS

AF:

0.784

Gnomad FIN

AF:

0.884

Gnomad MID

AF:

0.755

Gnomad NFE

AF:

0.856

Gnomad OTH

AF:

0.842

GnomAD3 exomes

AF:

0.858

AC:

197631

AN:

230206

Hom.:

85434

AF XY:

0.851

AC XY:

107039

AN XY:

125836

show subpopulations

Gnomad AFR exome

AF:

0.919

Gnomad AMR exome

AF:

0.926

Gnomad ASJ exome

AF:

0.815

Gnomad EAS exome

AF:

0.854

Gnomad SAS exome

AF:

0.780

Gnomad FIN exome

AF:

0.880

Gnomad NFE exome

AF:

0.852

Gnomad OTH exome

AF:

0.858

GnomAD4 exome

AF:

0.860

AC:

1206601

AN:

1403448

Hom.:

519854

Cov.:

AF XY:

0.857

AC XY:

599130

AN XY:

699274

show subpopulations

Gnomad4 AFR exome

AF:

0.919

Gnomad4 AMR exome

AF:

0.923

Gnomad4 ASJ exome

AF:

0.813

Gnomad4 EAS exome

AF:

0.878

Gnomad4 SAS exome

AF:

0.785

Gnomad4 FIN exome

AF:

0.888

Gnomad4 NFE exome

AF:

0.861

Gnomad4 OTH exome

AF:

0.852

GnomAD4 genome

AF:

0.873

AC:

130478

AN:

149478

Hom.:

57027

Cov.:

AF XY:

0.872

AC XY:

63755

AN XY:

73082

show subpopulations

Gnomad4 AFR

AF:

0.908

Gnomad4 AMR

AF:

0.901

Gnomad4 ASJ

AF:

0.805

Gnomad4 EAS

AF:

0.867

Gnomad4 SAS

AF:

0.785

Gnomad4 FIN

AF:

0.884

Gnomad4 NFE

AF:

0.856

Gnomad4 OTH

AF:

0.842

Alfa

AF:

0.854

Hom.:

8177

Bravo

AF:

0.887

Asia WGS

AF:

0.805

AC:

2717

AN:

3372

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

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	Labcorp Genetics (formerly Invitae), Labcorp	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

- -

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

-0.84

CADD

Benign

1.4

DANN

Benign

0.24

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

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