rs34897046

Variant names:

• chr4-55459198-G-C
• rs34897046
• NM_004898.4:c.623C>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.623C>G​(p.Ser208Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,610,720 control chromosomes in the GnomAD database, including 2,182 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 0.034 (103 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2079 hom.)
• Consequence: CLOCK NM_004898.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 24 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 (MetaRNN=0.0031000078).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.623C>G	p.Ser208Cys	missense_variant	Exon 10 of 23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.623C>G	p.Ser208Cys	missense_variant	Exon 10 of 23	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.623C>G	p.Ser208Cys	missense_variant	Exon 9 of 22	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.623C>G	p.Ser208Cys	missense_variant	Exon 11 of 24	1		ENSP00000370723.1
CLOCK	ENST00000506747.5	n.913C>G		non_coding_transcript_exon_variant	Exon 9 of 13	1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5131 AN: 152182 Hom.: 102 Cov.: 32

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0346 AC: 8671 AN: 250640 AF XY: 0.0360

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.0157

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0368

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0492 AC: 71765 AN: 1458422 Hom.: 2079 Cov.: 30 AF XY: 0.0485 AC XY: 35219 AN XY: 725708

African (AFR) AF: 0.00661 AC: 221 AN: 33432

American (AMR) AF: 0.0171 AC: 762 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39640

South Asian (SAS) AF: 0.0279 AC: 2400 AN: 86160

European-Finnish (FIN) AF: 0.0378 AC: 2017 AN: 53396

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5754

European-Non Finnish (NFE) AF: 0.0573 AC: 63564 AN: 1108926

Other (OTH) AF: 0.0395 AC: 2383 AN: 60310

GnomAD4 genome AF: 0.0337 AC: 5131 AN: 152298 Hom.: 103 Cov.: 32 AF XY: 0.0328 AC XY: 2440 AN XY: 74478

African (AFR) AF: 0.00987 AC: 410 AN: 41554

American (AMR) AF: 0.0261 AC: 399 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0273 AC: 132 AN: 4828

European-Finnish (FIN) AF: 0.0379 AC: 402 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0537 AC: 3654 AN: 68020

Other (OTH) AF: 0.0227 AC: 48 AN: 2116

Alfa AF: 0.0462 Hom.: 151

Bravo AF: 0.0314

TwinsUK AF: 0.0618 AC: 229

ALSPAC AF: 0.0605 AC: 233

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0518 AC: 445

ExAC AF: 0.0349 AC: 4232

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0473

EpiControl AF: 0.0454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;.
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
PhyloP100		9.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.013	D;D;D
Sift4G	Benign	0.069	T;T;T
Polyphen		0.71	P;P;P
Vest4		0.18
MPC		0.67
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.33
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: rs34897046; hg19: chr4-56325365; COSMIC: COSV104401540; COSMIC: COSV104401540;