chr21-46003475-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001848.3(COL6A1):c.2549G>A(p.Arg850His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,608,614 control chromosomes in the GnomAD database, including 75,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R850S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 8173 hom., cov: 34)

Exomes 𝑓: 0.30 ( 67671 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.118

Publications

43 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007473856).

BP6

Variant 21-46003475-G-A is Benign according to our data. Variant chr21-46003475-G-A is described in ClinVar as Benign. ClinVar VariationId is 93861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.2549G>A	p.Arg850His	missense_variant	Exon 35 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.2549G>A	p.Arg850His	missense_variant	Exon 35 of 35	1	NM_001848.3	ENSP00000355180.3		P12109

Frequencies

GnomAD3 genomes

AF:

0.321

AC:

48807

AN:

152078

Hom.:

8165

Cov.:

show subpopulations

Gnomad AFR

AF:

0.404

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.323

Gnomad ASJ

AF:

0.230

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.283

AC:

68262

AN:

240858

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.274

Gnomad NFE exome

AF:

0.306

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.302

AC:

439372

AN:

1456418

Hom.:

67671

Cov.:

AF XY:

0.298

AC XY:

216249

AN XY:

724694

show subpopulations

African (AFR)

AF:

0.408

AC:

13646

AN:

33460

American (AMR)

AF:

0.299

AC:

13329

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

6075

AN:

26080

East Asian (EAS)

AF:

0.189

AC:

7486

AN:

39676

South Asian (SAS)

AF:

0.231

AC:

19948

AN:

86200

European-Finnish (FIN)

AF:

0.272

AC:

13296

AN:

48812

Middle Eastern (MID)

AF:

0.250

AC:

1439

AN:

5764

European-Non Finnish (NFE)

AF:

0.312

AC:

347097

AN:

1111476

Other (OTH)

AF:

0.283

AC:

17056

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

20357

40715

61072

81430

101787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11344

22688

34032

45376

56720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.321

AC:

48847

AN:

152196

Hom.:

8173

Cov.:

AF XY:

0.319

AC XY:

23765

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.404

AC:

16784

AN:

41530

American (AMR)

AF:

0.324

AC:

4957

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

798

AN:

3466

East Asian (EAS)

AF:

0.160

AC:

825

AN:

5168

South Asian (SAS)

AF:

0.218

AC:

1052

AN:

4824

European-Finnish (FIN)

AF:

0.277

AC:

2942

AN:

10614

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.304

AC:

20640

AN:

67974

Other (OTH)

AF:

0.295

AC:

622

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1745

3490

5235

6980

8725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.303

Hom.:

29954

Bravo

AF:

0.330

TwinsUK

AF:

0.305

AC:

1131

ALSPAC

AF:

0.311

AC:

1197

ESP6500AA

AF:

0.398

AC:

1739

ESP6500EA

AF:

0.309

AC:

2627

ExAC

AF:

0.283

AC:

34130

Asia WGS

AF:

0.178

AC:

622

AN:

3478

EpiCase

AF:

0.305

EpiControl

AF:

0.301

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 07, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 17, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Collagen 6-related myopathy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

PhyloP100

-0.12

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;.

REVEL

Benign

0.13

Sift

Benign

0.16

T;.

Sift4G

Benign

0.12

T;T

Polyphen

0.0020

B;.

Vest4

0.055

MPC

0.28

ClinPred

0.0042

GERP RS

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.025

gMVP

0.32

Mutation Taster

=100/0

polymorphism (auto)

(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

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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