chr21-45981846-C-G

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.-5C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,574,586 control chromosomes in the GnomAD database, including 216,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 18376 hom., cov: 24)

Exomes 𝑓: 0.52 ( 198437 hom. )

Consequence

COL6A1
NM_001848.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.257

Publications

15 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=-0.9).

BP6

Variant 21-45981846-C-G is Benign according to our data. Variant chr21-45981846-C-G is described in ClinVar as Benign. ClinVar VariationId is 93792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.-5C>G		5_prime_UTR_variant	Exon 1 of 35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.-5C>G		5_prime_UTR_variant	Exon 1 of 35	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes

AF:

0.477

AC:

71156

AN:

149192

Hom.:

18365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.284

Gnomad AMI

AF:

0.605

Gnomad AMR

AF:

0.556

Gnomad ASJ

AF:

0.583

Gnomad EAS

AF:

0.770

Gnomad SAS

AF:

0.621

Gnomad FIN

AF:

0.562

Gnomad MID

AF:

0.660

Gnomad NFE

AF:

0.521

Gnomad OTH

AF:

0.539

GnomAD2 exomes

AF:

0.555

AC:

104340

AN:

188092

AF XY:

0.557

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.604

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.774

Gnomad FIN exome

AF:

0.557

Gnomad NFE exome

AF:

0.516

Gnomad OTH exome

AF:

0.576

GnomAD4 exome

AF:

0.523

AC:

744998

AN:

1425282

Hom.:

198437

Cov.:

AF XY:

0.527

AC XY:

372074

AN XY:

706378

show subpopulations

African (AFR)

AF:

0.272

AC:

8843

AN:

32534

American (AMR)

AF:

0.604

AC:

24454

AN:

40506

Ashkenazi Jewish (ASJ)

AF:

0.580

AC:

14811

AN:

25526

East Asian (EAS)

AF:

0.748

AC:

27963

AN:

37406

South Asian (SAS)

AF:

0.606

AC:

49465

AN:

81590

European-Finnish (FIN)

AF:

0.563

AC:

27755

AN:

49316

Middle Eastern (MID)

AF:

0.611

AC:

2678

AN:

4386

European-Non Finnish (NFE)

AF:

0.509

AC:

557304

AN:

1095124

Other (OTH)

AF:

0.539

AC:

31725

AN:

58894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

15688

31376

47064

62752

78440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16182

32364

48546

64728

80910

<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:

0.477

AC:

71194

AN:

149304

Hom.:

18376

Cov.:

AF XY:

0.482

AC XY:

35079

AN XY:

72772

show subpopulations

African (AFR)

AF:

0.284

AC:

11522

AN:

40562

American (AMR)

AF:

0.555

AC:

8361

AN:

15054

Ashkenazi Jewish (ASJ)

AF:

0.583

AC:

2013

AN:

3452

East Asian (EAS)

AF:

0.770

AC:

3768

AN:

4892

South Asian (SAS)

AF:

0.619

AC:

2865

AN:

4630

European-Finnish (FIN)

AF:

0.562

AC:

5779

AN:

10286

Middle Eastern (MID)

AF:

0.662

AC:

192

AN:

290

European-Non Finnish (NFE)

AF:

0.521

AC:

35021

AN:

67164

Other (OTH)

AF:

0.544

AC:

1132

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1508

3016

4523

6031

7539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

654

1308

1962

2616

3270

<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:

0.490

Hom.:

5441

Bravo

AF:

0.470

Asia WGS

AF:

0.703

AC:

2443

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 20, 2016

Eurofins Ntd Llc (ga)

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. -

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

-0.90

CADD

Benign

8.7

(source)

DANN

Benign

0.48

PhyloP100

0.26

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=298/2

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