4-55515830-C-G

Variant names:

• chr4-55515830-C-G
• rs6850524
• NM_004898.4:c.-289-5765G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 43 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-289-5765G>C		intron_variant	Intron 1 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.-289-5765G>C		intron_variant	Intron 1 of 22	1	NM_004898.4	ENSP00000426983.1

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

African (AFR) AF: 0.359 AC: 14864 AN: 41458

American (AMR) AF: 0.643 AC: 9822 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2088 AN: 3470

East Asian (EAS) AF: 0.679 AC: 3517 AN: 5178

South Asian (SAS) AF: 0.658 AC: 3174 AN: 4826

European-Finnish (FIN) AF: 0.688 AC: 7274 AN: 10570

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40330 AN: 67978

Other (OTH) AF: 0.536 AC: 1128 AN: 2106

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
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6850524; hg19: chr4-56381997;