4-55487920-C-G

Variant names:

• chr4-55487920-C-G
• rs4864542
• NM_004898.4:c.-44+1454G>C

Variant summary

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

The ENST00000513440.6(CLOCK):​c.-44+1454G>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 151,876 control chromosomes in the GnomAD database, including 9,375 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 (9375 hom., cov: 32)
• Consequence: CLOCK ENST00000513440.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.805
• Publications: 11 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000513440.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.-44+1454G>C		intron	N/A	NP_004889.1
	CLOCK	NM_001267843.2		c.-200-1371G>C		intron	N/A	NP_001254772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.-44+1454G>C		intron	N/A	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.-44+1454G>C		intron	N/A	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.-200-1371G>C		intron	N/A	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51350 AN: 151756 Hom.: 9366 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.338 AC: 51360 AN: 151876 Hom.: 9375 Cov.: 32 AF XY: 0.346 AC XY: 25669 AN XY: 74236

African (AFR) AF: 0.198 AC: 8209 AN: 41418

American (AMR) AF: 0.439 AC: 6696 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1450 AN: 3466

East Asian (EAS) AF: 0.581 AC: 3002 AN: 5166

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4808

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

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24642 AN: 67922

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

Alfa AF: 0.207 Hom.: 463

Bravo AF: 0.337

Asia WGS AF: 0.474 AC: 1648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.59
PhyloP100		-0.81
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: rs4864542; hg19: chr4-56354087;