4-55541180-G-T

Variant names:

• chr4-55541180-G-T
• rs7698022
• NM_004898.4:c.-290+5602C>A

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+5602C>A 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 152,118 control chromosomes in the GnomAD database, including 43,548 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 (43548 hom., cov: 33)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121
• Publications: 13 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.-290+5602C>A		intron	N/A	NP_004889.1
	CLOCK	NM_001267843.2		c.-447+4273C>A		intron	N/A	NP_001254772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.-290+5602C>A		intron	N/A	ENSP00000426983.1
	CLOCK	ENST00000381322.5	TSL:1	c.-447+4273C>A		intron	N/A	ENSP00000370723.1
	CLOCK	ENST00000435527.6	TSL:3	c.-136+5302C>A		intron	N/A	ENSP00000396649.2

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114586 AN: 152000 Hom.: 43508 Cov.: 33

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: 0.630

Gnomad FIN AF: 0.645

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: 114679 AN: 152118 Hom.: 43548 Cov.: 33 AF XY: 0.749 AC XY: 55681 AN XY: 74356

African (AFR) AF: 0.828 AC: 34383 AN: 41522

American (AMR) AF: 0.766 AC: 11712 AN: 15280

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

East Asian (EAS) AF: 0.901 AC: 4665 AN: 5180

South Asian (SAS) AF: 0.628 AC: 3026 AN: 4816

European-Finnish (FIN) AF: 0.645 AC: 6802 AN: 10548

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

European-Non Finnish (NFE) AF: 0.720 AC: 48957 AN: 67980

Other (OTH) AF: 0.756 AC: 1598 AN: 2114

Alfa AF: 0.695 Hom.: 6123

Bravo AF: 0.774

Asia WGS AF: 0.738 AC: 2555 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.1
DANN	Benign	0.55
PhyloP100		0.12
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: rs7698022; hg19: chr4-56407347;