Genetic Variant NM_004898.4:c.349-68A>G (chr4-55470874-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.349-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,096,044 control chromosomes in the GnomAD database, including 82,694 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 0.34 ( 9374 hom., cov: 32)

Exomes 𝑓: 0.39 ( 73320 hom. )

Consequence

CLOCK
NM_004898.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.704

Publications

25 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=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4 link	c.349-68A>G		intron_variant	Intron 7 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.349-68A>G		intron_variant	Intron 7 of 22	1	NM_004898.4	ENSP00000426983.1		O15516

Frequencies

GnomAD3 genomes

AF:

0.338

AC:

51373

AN:

151892

Hom.:

9365

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.439

Gnomad ASJ

AF:

0.419

Gnomad EAS

AF:

0.580

Gnomad SAS

AF:

0.440

Gnomad FIN

AF:

0.395

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.337

GnomAD4 exome

AF:

0.388

AC:

365854

AN:

944034

Hom.:

73320

AF XY:

0.389

AC XY:

190842

AN XY:

490550

show subpopulations

African (AFR)

AF:

0.190

AC:

4225

AN:

22210

American (AMR)

AF:

0.504

AC:

18846

AN:

37422

Ashkenazi Jewish (ASJ)

AF:

0.434

AC:

9535

AN:

21970

East Asian (EAS)

AF:

0.610

AC:

22639

AN:

37120

South Asian (SAS)

AF:

0.445

AC:

31267

AN:

70212

European-Finnish (FIN)

AF:

0.401

AC:

20398

AN:

50918

Middle Eastern (MID)

AF:

0.347

AC:

1265

AN:

3642

European-Non Finnish (NFE)

AF:

0.367

AC:

241170

AN:

657802

Other (OTH)

AF:

0.386

AC:

16509

AN:

42738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

10900

21801

32701

43602

54502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5954

11908

17862

23816

29770

<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:

0.338

AC:

51382

AN:

152010

Hom.:

9374

Cov.:

AF XY:

0.345

AC XY:

25651

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.198

AC:

8217

AN:

41472

American (AMR)

AF:

0.439

AC:

6709

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.419

AC:

1453

AN:

3468

East Asian (EAS)

AF:

0.580

AC:

2995

AN:

5164

South Asian (SAS)

AF:

0.439

AC:

2109

AN:

4806

European-Finnish (FIN)

AF:

0.395

AC:

4168

AN:

10552

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24635

AN:

67946

Other (OTH)

AF:

0.342

AC:

723

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1682

3364

5045

6727

8409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

520

1040

1560

2080

2600

<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:

0.357

Hom.:

4633

Bravo

AF:

0.337

Asia WGS

AF:

0.474

AC:

1647

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

0.70

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