4-55458985-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_004898.4(CLOCK):c.699T>C(p.Phe233=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,613,848 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (48 hom.)
• Consequence: CLOCK NM_004898.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-55458985-A-G is Benign according to our data. Variant chr4-55458985-A-G is described in ClinVar as [Benign]. Clinvar id is 775979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2189/152350) while in subpopulation AFR AF= 0.0504 (2096/41570). AF 95% confidence interval is 0.0486. There are 53 homozygotes in gnomad4. There are 1016 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2187 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.699T>C	p.Phe233=	synonymous_variant	11/23	ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.699T>C	p.Phe233=	synonymous_variant	11/23	1	NM_004898.4	P1
CLOCK	ENST00000309964.8	c.699T>C	p.Phe233=	synonymous_variant	10/22	1		P1
CLOCK	ENST00000381322.5	c.699T>C	p.Phe233=	synonymous_variant	12/24	1		P1
CLOCK	ENST00000506747.5	n.989T>C		non_coding_transcript_exon_variant	10/13	1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2187 AN: 152232 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00355 AC: 892 AN: 251128 Hom.: 16 AF XY: 0.00258 AC XY: 350 AN XY: 135716

Gnomad AFR exome AF: 0.0496

Gnomad AMR exome AF: 0.00217

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: 0.0000440

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00131 AC: 1916 AN: 1461498 Hom.: 48 Cov.: 31 AF XY: 0.00112 AC XY: 811 AN XY: 727072

Gnomad4 AFR exome AF: 0.0478

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.0144 AC: 2189 AN: 152350 Hom.: 53 Cov.: 32 AF XY: 0.0136 AC XY: 1016 AN XY: 74504

Gnomad4 AFR AF: 0.0504

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00810 Hom.: 23

Bravo AF: 0.0163

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	9.3
Dann	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34401111; hg19: chr4-56325152;