chr4-55501955-G-C

Variant names:

• chr4-55501955-G-C
• rs12648271
• NM_004898.4:c.-136+7957C>G

Variant summary

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

The NM_004898.4(CLOCK):​c.-136+7957C>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 152,030 control chromosomes in the GnomAD database, including 5,690 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 (5690 hom., cov: 33)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.312
• Publications: 8 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]

Y_RNA (HGNC:):

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: 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.-136+7957C>G		intron	N/A	NP_004889.1
	CLOCK	NM_001267843.2		c.-293+7957C>G		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.-136+7957C>G		intron	N/A	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.-136+7957C>G		intron	N/A	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.-293+7957C>G		intron	N/A	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36677 AN: 151914 Hom.: 5680 Cov.: 33

Gnomad AFR AF: 0.0553

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.232

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: 36691 AN: 152030 Hom.: 5690 Cov.: 33 AF XY: 0.250 AC XY: 18603 AN XY: 74312

African (AFR) AF: 0.0551 AC: 2286 AN: 41472

American (AMR) AF: 0.371 AC: 5675 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1263 AN: 3470

East Asian (EAS) AF: 0.581 AC: 3008 AN: 5174

South Asian (SAS) AF: 0.384 AC: 1851 AN: 4818

European-Finnish (FIN) AF: 0.307 AC: 3237 AN: 10544

Middle Eastern (MID) AF: 0.233 AC: 68 AN: 292

European-Non Finnish (NFE) AF: 0.273 AC: 18525 AN: 67964

Other (OTH) AF: 0.256 AC: 539 AN: 2106

Alfa AF: 0.141 Hom.: 287

Bravo AF: 0.240

Asia WGS AF: 0.446 AC: 1552 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	2.7
DANN	Benign	0.41
PhyloP100		0.31
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: rs12648271; hg19: chr4-56368122;