NM_004898.4:c.48-1421G>A

Variant names:

• chr4-55481120-C-T
• rs11735267
• NM_004898.4:c.48-1421G>A

Variant summary

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

The NM_004898.4(CLOCK):​c.48-1421G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.689 in 151,850 control chromosomes in the GnomAD database, including 36,293 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 0.69 (36293 hom., cov: 29)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.48-1421G>A		intron_variant	Intron 4 of 22	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.48-1421G>A		intron_variant	Intron 4 of 22	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104513 AN: 151730 Hom.: 36248 Cov.: 29

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.657

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.661

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

GnomAD4 genome AF: 0.689 AC: 104604 AN: 151850 Hom.: 36293 Cov.: 29 AF XY: 0.697 AC XY: 51722 AN XY: 74196

African (AFR) AF: 0.732 AC: 30295 AN: 41404

American (AMR) AF: 0.710 AC: 10844 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 2277 AN: 3464

East Asian (EAS) AF: 0.681 AC: 3481 AN: 5112

South Asian (SAS) AF: 0.812 AC: 3904 AN: 4806

European-Finnish (FIN) AF: 0.751 AC: 7932 AN: 10556

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43777 AN: 67934

Other (OTH) AF: 0.664 AC: 1398 AN: 2106

Alfa AF: 0.685 Hom.: 4639

Bravo AF: 0.682

Asia WGS AF: 0.757 AC: 2633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.49
DANN	Benign	0.28
PhyloP100		-1.1
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: rs11735267; hg19: chr4-56347287;