4-55455650-C-G

Variant names:

• chr4-55455650-C-G
• rs1554483
• NM_004898.4:c.982+247G>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+247G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 151,980 control chromosomes in the GnomAD database, including 9,381 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 (9381 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 31 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.982+247G>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+247G>C		intron_variant	Intron 13 of 22	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.982+247G>C		intron_variant	Intron 12 of 21	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.982+247G>C		intron_variant	Intron 14 of 23	1		ENSP00000370723.1
CLOCK	ENST00000506747.5	n.1272+247G>C		intron_variant	Intron 12 of 12	1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51371 AN: 151862 Hom.: 9372 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.337

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

GnomAD4 genome AF: 0.338 AC: 51380 AN: 151980 Hom.: 9381 Cov.: 32 AF XY: 0.346 AC XY: 25671 AN XY: 74284

African (AFR) AF: 0.198 AC: 8210 AN: 41446

American (AMR) AF: 0.438 AC: 6690 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1451 AN: 3470

East Asian (EAS) AF: 0.583 AC: 3020 AN: 5178

South Asian (SAS) AF: 0.438 AC: 2114 AN: 4824

European-Finnish (FIN) AF: 0.395 AC: 4160 AN: 10524

Middle Eastern (MID) AF: 0.318 AC: 93 AN: 292

European-Non Finnish (NFE) AF: 0.363 AC: 24639 AN: 67962

Other (OTH) AF: 0.342 AC: 723 AN: 2114

Alfa AF: 0.347 Hom.: 1235

Bravo AF: 0.337

Asia WGS AF: 0.475 AC: 1648 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.39
PhyloP100		-0.054
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: rs1554483; hg19: chr4-56321817;