rs12649507

Variant names:

• chr4-55514317-G-A
• rs12649507
• NM_004898.4:c.-289-4252C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-55514317-G-A
• chr4-55514317-G-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.-289-4252C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 151,798 control chromosomes in the GnomAD database, including 7,630 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 0.30 (7630 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252
• Publications: 46 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-289-4252C>T		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.-289-4252C>T		intron_variant	Intron 1 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46188 AN: 151680 Hom.: 7621 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.413

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.304 AC: 46196 AN: 151798 Hom.: 7630 Cov.: 32 AF XY: 0.313 AC XY: 23190 AN XY: 74174

African (AFR) AF: 0.188 AC: 7797 AN: 41436

American (AMR) AF: 0.412 AC: 6293 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3468

East Asian (EAS) AF: 0.581 AC: 2997 AN: 5162

South Asian (SAS) AF: 0.412 AC: 1978 AN: 4802

European-Finnish (FIN) AF: 0.358 AC: 3763 AN: 10510

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 20955 AN: 67856

Other (OTH) AF: 0.319 AC: 670 AN: 2102

Alfa AF: 0.311 Hom.: 7138

Bravo AF: 0.306

Asia WGS AF: 0.465 AC: 1617 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.4
DANN	Benign	0.59
PhyloP100		0.25
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: rs12649507; hg19: chr4-56380484;