chr4-55487920-C-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(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 NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.805

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.-44+1454G>C		intron_variant	Intron 3 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.-44+1454G>C		intron_variant	Intron 3 of 22	1	NM_004898.4	ENSP00000426983.1

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

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.581

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.342

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.18
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs4864542; hg19: chr4-56354087;