4-55462689-A-C

Variant names:

• chr4-55462689-A-C
• rs4340844
• NM_004898.4:c.559+996T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004898.4(CLOCK):​c.559+996T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,092 control chromosomes in the GnomAD database, including 9,390 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 0.34 (9390 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.491
• Publications: 11 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.559+996T>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.559+996T>G		intron_variant	Intron 9 of 22	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.559+996T>G		intron_variant	Intron 8 of 21	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.559+996T>G		intron_variant	Intron 10 of 23	1		ENSP00000370723.1
CLOCK	ENST00000506747.5	n.849+996T>G		intron_variant	Intron 8 of 12	1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51416 AN: 151974 Hom.: 9381 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.583

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.338 AC: 51425 AN: 152092 Hom.: 9390 Cov.: 32 AF XY: 0.346 AC XY: 25692 AN XY: 74352

African (AFR) AF: 0.198 AC: 8226 AN: 41478

American (AMR) AF: 0.439 AC: 6704 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1455 AN: 3472

East Asian (EAS) AF: 0.582 AC: 3011 AN: 5170

South Asian (SAS) AF: 0.439 AC: 2119 AN: 4828

European-Finnish (FIN) AF: 0.395 AC: 4180 AN: 10582

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24636 AN: 67964

Other (OTH) AF: 0.342 AC: 722 AN: 2112

Alfa AF: 0.340 Hom.: 1169

Bravo AF: 0.337

Asia WGS AF: 0.475 AC: 1651 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		0.49
Mutation Taster		=99/1	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: rs4340844; hg19: chr4-56328856;