chr21-45986636-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001848.3(COL6A1):c.539A>G(p.Lys180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 in 1,552,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.60

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Bethlem myopathy 1A
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046704084).

BP6

Variant 21-45986636-A-G is Benign according to our data. Variant chr21-45986636-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283031.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.539A>G	p.Lys180Arg	missense_variant	Exon 4 of 35	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.539A>G	p.Lys180Arg	missense_variant	Exon 4 of 35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000157

AC:

AN:

159284

AF XY:

0.000167

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00245

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000482

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.0000685

AC:

AN:

1400844

Hom.:

Cov.:

AF XY:

0.0000680

AC XY:

AN XY:

691252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31712

American (AMR)

AF:

0.00

AC:

AN:

36296

Ashkenazi Jewish (ASJ)

AF:

0.00238

AC:

AN:

25206

East Asian (EAS)

AF:

0.00

AC:

AN:

35936

South Asian (SAS)

AF:

0.00

AC:

AN:

79378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000278

AC:

AN:

1080462

Other (OTH)

AF:

0.000103

AC:

AN:

58070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000988

AC:

AN:

151866

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41300

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000360

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000467

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Sep 14, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bethlem myopathy 1A

Benign:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.090

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.20

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.047

T;T

MetaSVM

Uncertain

0.56

MutationAssessor

Benign

0.67

N;.

PhyloP100

2.6

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.54

N;.

REVEL

Uncertain

0.59

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

1.0

D;.

Vest4

0.28

MutPred

0.71

Loss of ubiquitination at K180 (P = 0.0283);Loss of ubiquitination at K180 (P = 0.0283);

MVP

0.90

MPC

0.18

ClinPred

0.36

GERP RS

3.7

Varity_R

0.093

gMVP

0.64

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr21-45986636-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over