Variant rs34897046 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004898.4(CLOCK):c.623C>G(p.Ser208Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,610,720 control chromosomes in the GnomAD database, including 2,182 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.034 ( 103 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2079 hom. )

Consequence

CLOCK
NM_004898.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

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 made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031000078).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4 link	c.623C>G	p.Ser208Cys	missense_variant	10/23	ENST00000513440.6	NP_004889.1	O15516Q53EU0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLOCK	ENST00000513440.6 link	c.623C>G	p.Ser208Cys	missense_variant	10/23	1	NM_004898.4	ENSP00000426983.1	O15516
CLOCK	ENST00000309964.8 link	c.623C>G	p.Ser208Cys	missense_variant	9/22	1		ENSP00000308741.4	O15516
CLOCK	ENST00000381322.5 link	c.623C>G	p.Ser208Cys	missense_variant	11/24	1		ENSP00000370723.1	O15516
CLOCK	ENST00000506747.5 link	n.913C>G		non_coding_transcript_exon_variant	9/13	1

Frequencies

GnomAD3 genomes

AF:

0.0337

AC:

5131

AN:

152182

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00990

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0262

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.0379

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0537

Gnomad OTH

AF:

0.0229

GnomAD3 exomes

AF:

0.0346

AC:

8671

AN:

250640

Hom.:

213

AF XY:

0.0360

AC XY:

4877

AN XY:

135536

show subpopulations

Gnomad AFR exome

AF:

0.00867

Gnomad AMR exome

AF:

0.0157

Gnomad ASJ exome

AF:

0.0121

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0278

Gnomad FIN exome

AF:

0.0368

Gnomad NFE exome

AF:

0.0532

Gnomad OTH exome

AF:

0.0308

GnomAD4 exome

AF:

0.0492

AC:

71765

AN:

1458422

Hom.:

2079

Cov.:

AF XY:

0.0485

AC XY:

35219

AN XY:

725708

show subpopulations

Gnomad4 AFR exome

AF:

0.00661

Gnomad4 AMR exome

AF:

0.0171

Gnomad4 ASJ exome

AF:

0.0143

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0279

Gnomad4 FIN exome

AF:

0.0378

Gnomad4 NFE exome

AF:

0.0573

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.0337

AC:

5131

AN:

152298

Hom.:

103

Cov.:

AF XY:

0.0328

AC XY:

2440

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00987

Gnomad4 AMR

AF:

0.0261

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0273

Gnomad4 FIN

AF:

0.0379

Gnomad4 NFE

AF:

0.0537

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0462

Hom.:

151

Bravo

AF:

0.0314

TwinsUK

AF:

0.0618

AC:

229

ALSPAC

AF:

0.0605

AC:

233

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0518

AC:

445

ExAC

AF:

0.0349

AC:

4232

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0473

EpiControl

AF:

0.0454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;.

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;L

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.013

D;D;D

Sift4G

Benign

0.069

T;T;T

Polyphen

0.71

P;P;P

Vest4

0.18

MPC

0.67

ClinPred

0.027

GERP RS

5.9

Varity_R

0.17

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over