rs11932595

chr4-55457430-A-Gchr4-55457430-A-T

Variant summary

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

The NM_004898.4(CLOCK):c.793-1130T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 151,946 control chromosomes in the GnomAD database, including 11,698 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 0.39 (11698 hom., cov: 31)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.596

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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.793-1130T>C		intron_variant		ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.793-1130T>C		intron_variant		1	NM_004898.4	P1
CLOCK	ENST00000309964.8	c.793-1130T>C		intron_variant		1		P1
CLOCK	ENST00000381322.5	c.793-1130T>C		intron_variant		1		P1
CLOCK	ENST00000506747.5	n.1083-1130T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58797 AN: 151828 Hom.: 11683 Cov.: 31

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.386

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

GnomAD4 genome AF: 0.387 AC: 58848 AN: 151946 Hom.: 11698 Cov.: 31 AF XY: 0.388 AC XY: 28798 AN XY: 74258

Gnomad4 AFR AF: 0.378

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.413

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.433

Gnomad4 FIN AF: 0.455

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.384

Alfa AF: 0.389 Hom.: 10848

Bravo AF: 0.371

Asia WGS AF: 0.311 AC: 1081 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.1
Dann	Benign	0.83

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: rs11932595; hg19: chr4-56323597;