rs12649507

Positions:

• chr4-55514317-G-A
• chr4-55514317-G-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-289-4252C>T		intron_variant		ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.-289-4252C>T		intron_variant		1	NM_004898.4	ENSP00000426983	P1

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

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.405

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.319

Alfa AF: 0.312 Hom.: 6095

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12649507; hg19: chr4-56380484;