chr4-55479088-T-C

Variant names:

• chr4-55479088-T-C
• rs13102385
• NM_004898.4:c.108-125A>G

Variant summary

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

The NM_004898.4(CLOCK):​c.108-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 773,628 control chromosomes in the GnomAD database, including 163,059 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 0.58 (27588 hom., cov: 33)
  • Exomes 𝑓: 0.65 (135471 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300

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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.108-125A>G		intron_variant	Intron 5 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.108-125A>G		intron_variant	Intron 5 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88839 AN: 151886 Hom.: 27567 Cov.: 33

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.583

GnomAD4 exome AF: 0.654 AC: 406588 AN: 621624 Hom.: 135471 Cov.: 8 AF XY: 0.661 AC XY: 210268 AN XY: 318114

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.701

Gnomad4 ASJ exome AF: 0.668

Gnomad4 EAS exome AF: 0.746

Gnomad4 SAS exome AF: 0.808

Gnomad4 FIN exome AF: 0.742

Gnomad4 NFE exome AF: 0.635

Gnomad4 OTH exome AF: 0.645

GnomAD4 genome AF: 0.585 AC: 88873 AN: 152004 Hom.: 27588 Cov.: 33 AF XY: 0.597 AC XY: 44372 AN XY: 74316

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.680

Gnomad4 SAS AF: 0.811

Gnomad4 FIN AF: 0.751

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.587

Alfa AF: 0.631 Hom.: 7168

Bravo AF: 0.563

Asia WGS AF: 0.734 AC: 2545 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.78

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: rs13102385; hg19: chr4-56345255; COSMIC: COSV59402351; COSMIC: COSV59402351;