Variant chr4-55443825-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The ENST00000513440.6(CLOCK):c.1764T>C(p.Asn588=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,613,442 control chromosomes in the GnomAD database, including 358,738 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 0.69 ( 36338 hom., cov: 32)

Exomes 𝑓: 0.66 ( 322400 hom. )

Consequence

CLOCK
ENST00000513440.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.408

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:

TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

TMEM165 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP7

Synonymous conserved (PhyloP=-0.408 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4 linkuse as main transcript	c.1764T>C	p.Asn588=	synonymous_variant	20/23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6 linkuse as main transcript	c.1764T>C	p.Asn588=	synonymous_variant	20/23	1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes

AF:

0.689

AC:

104641

AN:

151924

Hom.:

36294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.732

Gnomad AMI

AF:

0.577

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.656

Gnomad EAS

AF:

0.684

Gnomad SAS

AF:

0.812

Gnomad FIN

AF:

0.752

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.644

Gnomad OTH

AF:

0.660

GnomAD3 exomes

AF:

0.696

AC:

174793

AN:

251220

Hom.:

61575

AF XY:

0.697

AC XY:

94614

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.738

Gnomad AMR exome

AF:

0.747

Gnomad ASJ exome

AF:

0.661

Gnomad EAS exome

AF:

0.679

Gnomad SAS exome

AF:

0.809

Gnomad FIN exome

AF:

0.746

Gnomad NFE exome

AF:

0.642

Gnomad OTH exome

AF:

0.667

GnomAD4 exome

AF:

0.662

AC:

967019

AN:

1461400

Hom.:

322400

Cov.:

AF XY:

0.666

AC XY:

484237

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.742

Gnomad4 AMR exome

AF:

0.740

Gnomad4 ASJ exome

AF:

0.664

Gnomad4 EAS exome

AF:

0.737

Gnomad4 SAS exome

AF:

0.808

Gnomad4 FIN exome

AF:

0.741

Gnomad4 NFE exome

AF:

0.638

Gnomad4 OTH exome

AF:

0.673

GnomAD4 genome

AF:

0.689

AC:

104730

AN:

152042

Hom.:

36338

Cov.:

AF XY:

0.697

AC XY:

51808

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.732

Gnomad4 AMR

AF:

0.710

Gnomad4 ASJ

AF:

0.656

Gnomad4 EAS

AF:

0.683

Gnomad4 SAS

AF:

0.813

Gnomad4 FIN

AF:

0.752

Gnomad4 NFE

AF:

0.644

Gnomad4 OTH

AF:

0.663

Alfa

AF:

0.651

Hom.:

22210

Bravo

AF:

0.682

Asia WGS

AF:

0.758

AC:

2639

AN:

3478

EpiCase

AF:

0.639

EpiControl

AF:

0.639

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.7

DANN

Benign

0.58

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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