rs12504300

chr4-55482360-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_004898.4(CLOCK):c.47+379C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,092 control chromosomes in the GnomAD database, including 5,683 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 0.24 (5683 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.434

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 -8 ACMG points.

• 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	UniProt
CLOCK	NM_004898.4	c.47+379C>G		intron_variant		ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.47+379C>G		intron_variant		1	NM_004898.4	P1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36664 AN: 151974 Hom.: 5673 Cov.: 32

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.241 AC: 36678 AN: 152092 Hom.: 5683 Cov.: 32 AF XY: 0.250 AC XY: 18589 AN XY: 74350

Gnomad4 AFR AF: 0.0551

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.273

Gnomad4 OTH AF: 0.256

Alfa AF: 0.254 Hom.: 691

Bravo AF: 0.240

Asia WGS AF: 0.446 AC: 1550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Pathogenic	26
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs12504300; hg19: chr4-56348527;