4-55460540-G-C

Variant names:

• chr4-55460540-G-C
• rs4580704
• NM_004898.4:c.560-1279C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.560-1279C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 152,108 control chromosomes in the GnomAD database, including 36,341 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 0.69 (36341 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.472
• Publications: 90 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=-1.01).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.560-1279C>G		intron_variant	Intron 9 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.560-1279C>G		intron_variant	Intron 9 of 22	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.560-1279C>G		intron_variant	Intron 8 of 21	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.560-1279C>G		intron_variant	Intron 10 of 23	1		ENSP00000370723.1
CLOCK	ENST00000506747.5	n.850-1279C>G		intron_variant	Intron 8 of 12	1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104663 AN: 151990 Hom.: 36297 Cov.: 32

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.689 AC: 104752 AN: 152108 Hom.: 36341 Cov.: 32 AF XY: 0.697 AC XY: 51815 AN XY: 74358

African (AFR) AF: 0.731 AC: 30354 AN: 41508

American (AMR) AF: 0.709 AC: 10838 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2278 AN: 3470

East Asian (EAS) AF: 0.681 AC: 3515 AN: 5162

South Asian (SAS) AF: 0.813 AC: 3922 AN: 4824

European-Finnish (FIN) AF: 0.752 AC: 7965 AN: 10592

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43783 AN: 67962

Other (OTH) AF: 0.663 AC: 1399 AN: 2110

Alfa AF: 0.609 Hom.: 2001

Bravo AF: 0.682

Asia WGS AF: 0.757 AC: 2633 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	1.2
DANN	Benign	0.38
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4580704; hg19: chr4-56326707;