4-55535530-C-G

Variant names:

• chr4-55535530-C-G
• rs7660668
• NM_004898.4:c.-290+11252G>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.-290+11252G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 151,914 control chromosomes in the GnomAD database, including 43,487 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 0.75 (43487 hom., cov: 31)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-290+11252G>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.-290+11252G>C		intron_variant	Intron 1 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114428 AN: 151796 Hom.: 43447 Cov.: 31

Gnomad AFR AF: 0.828

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.900

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.754

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

GnomAD4 genome AF: 0.754 AC: 114521 AN: 151914 Hom.: 43487 Cov.: 31 AF XY: 0.749 AC XY: 55583 AN XY: 74228

African (AFR) AF: 0.828 AC: 34307 AN: 41424

American (AMR) AF: 0.767 AC: 11698 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2651 AN: 3472

East Asian (EAS) AF: 0.900 AC: 4655 AN: 5170

South Asian (SAS) AF: 0.629 AC: 3023 AN: 4808

European-Finnish (FIN) AF: 0.644 AC: 6766 AN: 10506

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48946 AN: 67966

Other (OTH) AF: 0.755 AC: 1592 AN: 2108

Alfa AF: 0.722 Hom.: 4647

Bravo AF: 0.774

Asia WGS AF: 0.738 AC: 2561 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.90
DANN	Benign	0.29
PhyloP100		-1.1
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: rs7660668; hg19: chr4-56401697;