rs2412648

Variant names:

• chr4-55454900-T-G
• rs2412648
• NM_004898.4:c.982+997A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.982+997A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 127,828 control chromosomes in the GnomAD database, including 7,290 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 0.35 (7290 hom., cov: 21)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 16 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 = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.982+997A>C		intron_variant	Intron 13 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.982+997A>C		intron_variant	Intron 13 of 22	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.982+997A>C		intron_variant	Intron 12 of 21	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.982+997A>C		intron_variant	Intron 14 of 23	1		ENSP00000370723.1
CLOCK	ENST00000506747.5	n.1272+997A>C		intron_variant	Intron 12 of 12	1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 44480 AN: 127802 Hom.: 7281 Cov.: 21

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.461

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.348 AC: 44490 AN: 127828 Hom.: 7290 Cov.: 21 AF XY: 0.366 AC XY: 22130 AN XY: 60546

African (AFR) AF: 0.233 AC: 7291 AN: 31250

American (AMR) AF: 0.503 AC: 5924 AN: 11774

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1387 AN: 3340

East Asian (EAS) AF: 0.630 AC: 2837 AN: 4504

South Asian (SAS) AF: 0.461 AC: 1875 AN: 4068

European-Finnish (FIN) AF: 0.515 AC: 3467 AN: 6738

Middle Eastern (MID) AF: 0.454 AC: 88 AN: 194

European-Non Finnish (NFE) AF: 0.327 AC: 20750 AN: 63386

Other (OTH) AF: 0.366 AC: 627 AN: 1714

Alfa AF: 0.314 Hom.: 4096

Bravo AF: 0.305

Asia WGS AF: 0.467 AC: 1623 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	3.3
DANN	Benign	0.76
PhyloP100		-1.9
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: rs2412648; hg19: chr4-56321067;