NM_004898.4:c.349-1820C>T

Variant names:

• chr4-55472626-G-A
• rs11931061
• NM_004898.4:c.349-1820C>T

Variant summary

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

The NM_004898.4(CLOCK):​c.349-1820C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.585 in 151,992 control chromosomes in the GnomAD database, including 27,624 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 0.59 (27624 hom., cov: 31)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.667
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.349-1820C>T		intron	N/A	NP_004889.1
	CLOCK	NM_001267843.2		c.349-1820C>T		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.349-1820C>T		intron	N/A	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.349-1820C>T		intron	N/A	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.349-1820C>T		intron	N/A	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88925 AN: 151874 Hom.: 27603 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.810

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.583

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

GnomAD4 genome AF: 0.585 AC: 88959 AN: 151992 Hom.: 27624 Cov.: 31 AF XY: 0.598 AC XY: 44414 AN XY: 74288

African (AFR) AF: 0.372 AC: 15417 AN: 41438

American (AMR) AF: 0.673 AC: 10265 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2275 AN: 3468

East Asian (EAS) AF: 0.680 AC: 3507 AN: 5156

South Asian (SAS) AF: 0.811 AC: 3913 AN: 4824

European-Finnish (FIN) AF: 0.752 AC: 7953 AN: 10576

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.643 AC: 43697 AN: 67958

Other (OTH) AF: 0.587 AC: 1238 AN: 2110

Alfa AF: 0.617 Hom.: 92011

Bravo AF: 0.564

Asia WGS AF: 0.735 AC: 2556 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.0
DANN	Benign	0.60
PhyloP100		-0.67
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: rs11931061; hg19: chr4-56338793;