chr4-55476159-G-A

Position:

• chr4-55476159-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.257-105C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 764,306 control chromosomes in the GnomAD database, including 59,600 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 (9385 hom., cov: 31)
  • Exomes 𝑓: 0.40 (50215 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105

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]

CLOCK (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• 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/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.257-105C>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.257-105C>T		intron_variant		1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51375 AN: 151824 Hom.: 9376 Cov.: 31

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: 0.397

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.336

GnomAD4 exome AF: 0.396 AC: 242689 AN: 612364 Hom.: 50215 AF XY: 0.398 AC XY: 131033 AN XY: 329082

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.502

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.611

Gnomad4 SAS exome AF: 0.447

Gnomad4 FIN exome AF: 0.402

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.338 AC: 51384 AN: 151942 Hom.: 9385 Cov.: 31 AF XY: 0.346 AC XY: 25672 AN XY: 74254

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.397

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.342

Alfa AF: 0.364 Hom.: 5323

Bravo AF: 0.337

Asia WGS AF: 0.474 AC: 1648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs9312661; hg19: chr4-56342326; COSMIC: COSV59404201; COSMIC: COSV59404201;