Genetic Variant NM_004898.4:c.108-125A>G (chr4-55479088-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004898.4(CLOCK):c.108-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 773,628 control chromosomes in the GnomAD database, including 163,059 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.58 ( 27588 hom., cov: 33)

Exomes 𝑓: 0.65 ( 135471 hom. )

Consequence

CLOCK
NM_004898.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00300

Publications

8 publications found

Variant links:

Genes affected

CLOCK (HGNC:2082): (clock circadian regulator) The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

CLOCK links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4 link	c.108-125A>G		intron_variant	Intron 5 of 22	ENST00000513440.6	NP_004889.1	O15516Q53EU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6 link	c.108-125A>G		intron_variant	Intron 5 of 22	1	NM_004898.4	ENSP00000426983.1		O15516

Frequencies

GnomAD3 genomes

AF:

0.585

AC:

88839

AN:

151886

Hom.:

27567

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.579

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.656

Gnomad EAS

AF:

0.681

Gnomad SAS

AF:

0.811

Gnomad FIN

AF:

0.751

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.643

Gnomad OTH

AF:

0.583

GnomAD4 exome

AF:

0.654

AC:

406588

AN:

621624

Hom.:

135471

Cov.:

AF XY:

0.661

AC XY:

210268

AN XY:

318114

show subpopulations

African (AFR)

AF:

0.359

AC:

5571

AN:

15500

American (AMR)

AF:

0.701

AC:

11765

AN:

16774

Ashkenazi Jewish (ASJ)

AF:

0.668

AC:

9838

AN:

14730

East Asian (EAS)

AF:

0.746

AC:

22670

AN:

30376

South Asian (SAS)

AF:

0.808

AC:

33854

AN:

41892

European-Finnish (FIN)

AF:

0.742

AC:

24302

AN:

32756

Middle Eastern (MID)

AF:

0.597

AC:

1344

AN:

2250

European-Non Finnish (NFE)

AF:

0.635

AC:

277409

AN:

436574

Other (OTH)

AF:

0.645

AC:

19835

AN:

30772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

6535

13070

19606

26141

32676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4892

9784

14676

19568

24460

<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:

0.585

AC:

88873

AN:

152004

Hom.:

27588

Cov.:

AF XY:

0.597

AC XY:

44372

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.371

AC:

15371

AN:

41476

American (AMR)

AF:

0.672

AC:

10267

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.656

AC:

2274

AN:

3468

East Asian (EAS)

AF:

0.680

AC:

3517

AN:

5172

South Asian (SAS)

AF:

0.811

AC:

3916

AN:

4826

European-Finnish (FIN)

AF:

0.751

AC:

7952

AN:

10586

Middle Eastern (MID)

AF:

0.568

AC:

166

AN:

292

European-Non Finnish (NFE)

AF:

0.643

AC:

43647

AN:

67896

Other (OTH)

AF:

0.587

AC:

1237

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1771

3543

5314

7086

8857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.629

Hom.:

13231

Bravo

AF:

0.563

Asia WGS

AF:

0.734

AC:

2545

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.7

(source)

DANN

Benign

0.78

PhyloP100

0.0030

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

Computational scores

Splicing

Publications

Other links and lift over