4-55458980-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004898.4(CLOCK):c.704G>A(p.Gly235Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: CLOCK NM_004898.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.62

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00960359).
• BP6: Variant 4-55458980-C-T is Benign according to our data. Variant chr4-55458980-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 726740.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.704G>A	p.Gly235Glu	missense_variant	11/23	ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.704G>A	p.Gly235Glu	missense_variant	11/23	1	NM_004898.4	P1
CLOCK	ENST00000309964.8	c.704G>A	p.Gly235Glu	missense_variant	10/22	1		P1
CLOCK	ENST00000381322.5	c.704G>A	p.Gly235Glu	missense_variant	12/24	1		P1
CLOCK	ENST00000506747.5	n.994G>A		non_coding_transcript_exon_variant	10/13	1

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251112 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135704

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000903 AC: 132 AN: 1461554 Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56 AN XY: 727080

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74448

Gnomad4 AFR AF: 0.00279

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000948

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.0095
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.80	T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.59
MVP		0.27
MPC		0.55
ClinPred		0.042	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.81

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: rs138755597; hg19: chr4-56325147;