rs9312661

Variant names:

• chr4-55476159-G-A
• rs9312661
• NM_004898.4:c.257-105C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.257-105C>T		intron_variant	Intron 6 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.257-105C>T		intron_variant	Intron 6 of 22	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

African (AFR) AF: 0.192 AC: 3216 AN: 16718

American (AMR) AF: 0.502 AC: 17956 AN: 35782

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 8660 AN: 19904

East Asian (EAS) AF: 0.611 AC: 20408 AN: 33392

South Asian (SAS) AF: 0.447 AC: 28950 AN: 64814

European-Finnish (FIN) AF: 0.402 AC: 17412 AN: 43348

Middle Eastern (MID) AF: 0.340 AC: 1376 AN: 4046

European-Non Finnish (NFE) AF: 0.365 AC: 132452 AN: 362586

Other (OTH) AF: 0.386 AC: 12259 AN: 31774

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

African (AFR) AF: 0.198 AC: 8219 AN: 41454

American (AMR) AF: 0.438 AC: 6684 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1448 AN: 3456

East Asian (EAS) AF: 0.582 AC: 3001 AN: 5154

South Asian (SAS) AF: 0.439 AC: 2116 AN: 4824

European-Finnish (FIN) AF: 0.397 AC: 4183 AN: 10548

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24639 AN: 67946

Other (OTH) AF: 0.342 AC: 721 AN: 2110

Alfa AF: 0.362 Hom.: 5837

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
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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