chr21-45999689-G-A

Position:

chr21-45999689-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001848.3(COL6A1):c.1773G>A(p.Pro591=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00999 in 1,613,082 control chromosomes in the GnomAD database, including 657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 219 hom., cov: 30)

Exomes 𝑓: 0.0077 ( 438 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.662

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 21-45999689-G-A is Benign according to our data. Variant chr21-45999689-G-A is described in ClinVar as [Benign]. Clinvar id is 93828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45999689-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.662 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 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.1773G>A	p.Pro591=	synonymous_variant	27/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.1773G>A	p.Pro591=	synonymous_variant	27/35	1	NM_001848.3	P1
COL6A1	ENST00000466285.1 linkuse as main transcript	n.290G>A		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0323

AC:

4907

AN:

151854

Hom.:

219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.00488

Gnomad SAS

AF:

0.0625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000883

Gnomad OTH

AF:

0.0254

GnomAD3 exomes

AF:

0.0167

AC:

4175

AN:

249278

Hom.:

157

AF XY:

0.0173

AC XY:

2335

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.106

Gnomad AMR exome

AF:

0.00531

Gnomad ASJ exome

AF:

0.0248

Gnomad EAS exome

AF:

0.00524

Gnomad SAS exome

AF:

0.0589

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000914

Gnomad OTH exome

AF:

0.00936

GnomAD4 exome

AF:

0.00767

AC:

11200

AN:

1461110

Hom.:

438

Cov.:

AF XY:

0.00883

AC XY:

6419

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.109

Gnomad4 AMR exome

AF:

0.00582

Gnomad4 ASJ exome

AF:

0.0255

Gnomad4 EAS exome

AF:

0.00325

Gnomad4 SAS exome

AF:

0.0573

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000593

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.0324

AC:

4919

AN:

151972

Hom.:

219

Cov.:

AF XY:

0.0318

AC XY:

2363

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.00935

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.00450

Gnomad4 SAS

AF:

0.0630

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000883

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0342

Asia WGS

AF:

0.0420

AC:

148

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	GeneDx	Jul 20, 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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

-0.52

CADD

Benign

1.4

DANN

Benign

0.52

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