4-55515830-C-G

Position:

• chr4-55515830-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.-289-5765G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.545 in 152,070 control chromosomes in the GnomAD database, including 23,787 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 0.54 (23787 hom., cov: 33)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.798

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-289-5765G>C		intron_variant		ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.-289-5765G>C		intron_variant		1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes AF: 0.545 AC: 82832 AN: 151950 Hom.: 23769 Cov.: 33

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.562

Gnomad AMR AF: 0.642

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.680

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.531

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.545 AC: 82863 AN: 152070 Hom.: 23787 Cov.: 33 AF XY: 0.554 AC XY: 41212 AN XY: 74386

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.643

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.679

Gnomad4 SAS AF: 0.658

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.536

Alfa AF: 0.572 Hom.: 3111

Bravo AF: 0.530

Asia WGS AF: 0.663 AC: 2305 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.63
DANN	Benign	0.16

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6850524; hg19: chr4-56381997;