21-45997781-G-C

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.1524+19G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0868 in 1,569,514 control chromosomes in the GnomAD database, including 6,576 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.087 ( 639 hom., cov: 35)

Exomes 𝑓: 0.087 ( 5937 hom. )

Consequence

COL6A1
NM_001848.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.15

Publications

5 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 (BayesDel_noAF=-0.91).

BP6

Variant 21-45997781-G-C is Benign according to our data. Variant chr21-45997781-G-C is described in ClinVar as Benign. ClinVar VariationId is 93821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.1524+19G>C		intron_variant	Intron 22 of 34	ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.1524+19G>C		intron_variant	Intron 22 of 34	1	NM_001848.3	ENSP00000355180.3		P12109
COL6A1	ENST00000683550.1 link	n.299+19G>C		intron_variant	Intron 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0865

AC:

13161

AN:

152090

Hom.:

635

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0588

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.0729

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.0743

Gnomad FIN

AF:

0.107

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0825

Gnomad OTH

AF:

0.0970

GnomAD2 exomes

AF:

0.101

AC:

17918

AN:

177312

AF XY:

0.0970

show subpopulations

Gnomad AFR exome

AF:

0.0604

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.0656

Gnomad EAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.107

Gnomad NFE exome

AF:

0.0840

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.0869

AC:

123101

AN:

1417306

Hom.:

5937

Cov.:

AF XY:

0.0863

AC XY:

60507

AN XY:

701214

show subpopulations

African (AFR)

AF:

0.0554

AC:

1800

AN:

32472

American (AMR)

AF:

0.143

AC:

5546

AN:

38832

Ashkenazi Jewish (ASJ)

AF:

0.0647

AC:

1643

AN:

25382

East Asian (EAS)

AF:

0.209

AC:

7828

AN:

37392

South Asian (SAS)

AF:

0.0704

AC:

5698

AN:

80984

European-Finnish (FIN)

AF:

0.103

AC:

5075

AN:

49324

Middle Eastern (MID)

AF:

0.104

AC:

492

AN:

4714

European-Non Finnish (NFE)

AF:

0.0824

AC:

89773

AN:

1089600

Other (OTH)

AF:

0.0895

AC:

5246

AN:

58606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

5377

10753

16130

21506

26883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3392

6784

10176

13568

16960

<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:

0.0866

AC:

13177

AN:

152208

Hom.:

639

Cov.:

AF XY:

0.0876

AC XY:

6519

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0587

AC:

2440

AN:

41556

American (AMR)

AF:

0.129

AC:

1971

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0729

AC:

253

AN:

3472

East Asian (EAS)

AF:

0.199

AC:

1023

AN:

5148

South Asian (SAS)

AF:

0.0745

AC:

360

AN:

4830

European-Finnish (FIN)

AF:

0.107

AC:

1133

AN:

10616

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0826

AC:

5611

AN:

67958

Other (OTH)

AF:

0.100

AC:

212

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

647

1294

1941

2588

3235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

312

468

624

780

<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:

0.0432

Hom.:

Bravo

AF:

0.0883

Asia WGS

AF:

0.155

AC:

539

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

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 31, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Bethlem myopathy 1A

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.010

(source)

DANN

Benign

0.34

PhyloP100

-1.2

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