rs34897046

chr4-55459198-G-C

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (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/exons	MANE	UniProt
CLOCK	NM_004898.4	c.623C>G	p.Ser208Cys	missense_variant	10/23	ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.623C>G	p.Ser208Cys	missense_variant	10/23	1	NM_004898.4	P1
CLOCK	ENST00000309964.8	c.623C>G	p.Ser208Cys	missense_variant	9/22	1		P1
CLOCK	ENST00000381322.5	c.623C>G	p.Ser208Cys	missense_variant	11/24	1		P1
CLOCK	ENST00000506747.5	n.913C>G		non_coding_transcript_exon_variant	9/13	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

GnomAD3 exomes AF: 0.0346 AC: 8671 AN: 250640 Hom.: 213 AF XY: 0.0360 AC XY: 4877 AN XY: 135536

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 SAS exome AF: 0.0278

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

Gnomad4 AFR exome AF: 0.00661

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.0378

Gnomad4 NFE exome AF: 0.0573

Gnomad4 OTH exome AF: 0.0395

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

Gnomad4 AFR AF: 0.00987

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0273

Gnomad4 FIN AF: 0.0379

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0227

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
MutationTaster	Benign	1.0	D;D;D
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

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: rs34897046; hg19: chr4-56325365; COSMIC: COSV104401540; COSMIC: COSV104401540;