rs3817444

chr4-55509814-A-Cchr4-55509814-A-G

Variant summary

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

The NM_004898.4(CLOCK):c.-136+98T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 152,122 control chromosomes in the GnomAD database, including 36,800 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 0.69 (36799 hom., cov: 32)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47

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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.-136+98T>G		intron_variant		ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.-136+98T>G		intron_variant		1	NM_004898.4	P1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105277 AN: 152002 Hom.: 36748 Cov.: 32

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.712

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.682

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.598

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.661

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.693 AC: 105377 AN: 152120 Hom.: 36799 Cov.: 32 AF XY: 0.701 AC XY: 52122 AN XY: 74362

Gnomad4 AFR AF: 0.745

Gnomad4 AMR AF: 0.712

Gnomad4 ASJ AF: 0.657

Gnomad4 EAS AF: 0.681

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.664

Alfa AF: 0.650 Hom.: 62137

Bravo AF: 0.686

Asia WGS AF: 0.760 AC: 2644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.56
Dann	Benign	0.69

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: rs3817444; hg19: chr4-56375981;