NM_004898.4:c.47+379C>G

Variant names:

• chr4-55482360-G-C
• rs12504300
• NM_004898.4:c.47+379C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

The NM_004898.4(CLOCK):​c.47+379C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,092 control chromosomes in the GnomAD database, including 5,683 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 0.24 (5683 hom., cov: 32)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.434
• Publications: 13 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: Likely_benign. The variant received -6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.47+379C>G		intron	N/A	NP_004889.1	O15516
	CLOCK	NM_001267843.2		c.47+379C>G		intron	N/A	NP_001254772.1	O15516

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.47+379C>G		intron	N/A	ENSP00000426983.1	O15516
	CLOCK	ENST00000309964.8	TSL:1	c.47+379C>G		intron	N/A	ENSP00000308741.4	O15516
	CLOCK	ENST00000381322.5	TSL:1	c.47+379C>G		intron	N/A	ENSP00000370723.1	O15516

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36664 AN: 151974 Hom.: 5673 Cov.: 32

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.241 AC: 36678 AN: 152092 Hom.: 5683 Cov.: 32 AF XY: 0.250 AC XY: 18589 AN XY: 74350

African (AFR) AF: 0.0551 AC: 2289 AN: 41518

American (AMR) AF: 0.371 AC: 5667 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1265 AN: 3470

East Asian (EAS) AF: 0.580 AC: 2997 AN: 5166

South Asian (SAS) AF: 0.384 AC: 1853 AN: 4822

European-Finnish (FIN) AF: 0.307 AC: 3234 AN: 10544

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18524 AN: 67970

Other (OTH) AF: 0.256 AC: 541 AN: 2112

Alfa AF: 0.254 Hom.: 691

Bravo AF: 0.240

Asia WGS AF: 0.446 AC: 1550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Pathogenic	26
DANN	Benign	0.57
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.83		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12504300; hg19: chr4-56348527;