rs4864546

Variant names:

• chr4-55537960-G-A
• rs4864546
• NM_004898.4:c.-290+8822C>T

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+8822C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,840 control chromosomes in the GnomAD database, including 11,147 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 0.38 (11147 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.341
• Publications: 14 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.-290+8822C>T		intron	N/A	NP_004889.1	O15516
	CLOCK	NM_001267843.2		c.-447+7493C>T		intron	N/A	NP_001254772.1	O15516

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.-290+8822C>T		intron	N/A	ENSP00000426983.1	O15516
	CLOCK	ENST00000381322.5	TSL:1	c.-447+7493C>T		intron	N/A	ENSP00000370723.1	O15516
	CLOCK	ENST00000882369.1		c.-447+8822C>T		intron	N/A	ENSP00000552428.1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57912 AN: 151722 Hom.: 11139 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.420

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.382 AC: 57938 AN: 151840 Hom.: 11147 Cov.: 32 AF XY: 0.387 AC XY: 28751 AN XY: 74212

African (AFR) AF: 0.347 AC: 14364 AN: 41400

American (AMR) AF: 0.456 AC: 6949 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 1458 AN: 3470

East Asian (EAS) AF: 0.582 AC: 2997 AN: 5152

South Asian (SAS) AF: 0.440 AC: 2120 AN: 4816

European-Finnish (FIN) AF: 0.396 AC: 4163 AN: 10510

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.364 AC: 24708 AN: 67928

Other (OTH) AF: 0.381 AC: 805 AN: 2112

Alfa AF: 0.376 Hom.: 1977

Bravo AF: 0.387

Asia WGS AF: 0.484 AC: 1681 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	4.3
DANN	Benign	0.61
PhyloP100		-0.34
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: rs4864546; hg19: chr4-56404127;