4-55459020-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004898.4(CLOCK):c.674-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,594,972 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (13 hom.)
• Consequence: CLOCK NM_004898.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001503
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.87

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-55459020-T-C is Benign according to our data. Variant chr4-55459020-T-C is described in ClinVar as [Benign]. Clinvar id is 720262.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00159 (2288/1442672) while in subpopulation MID AF= 0.0223 (128/5734). AF 95% confidence interval is 0.0192. There are 13 homozygotes in gnomad4_exome. There are 1263 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd at 344 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.674-10A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.674-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004898.4	P1
CLOCK	ENST00000309964.8	c.674-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1		P1
CLOCK	ENST00000381322.5	c.674-10A>G		splice_polypyrimidine_tract_variant, intron_variant		1		P1
CLOCK	ENST00000506747.5	n.964-10A>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00245 AC: 614 AN: 251124 Hom.: 3 AF XY: 0.00265 AC XY: 359 AN XY: 135696

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00159 AC: 2288 AN: 1442672 Hom.: 13 Cov.: 27 AF XY: 0.00176 AC XY: 1263 AN XY: 718990

Gnomad4 AFR exome AF: 0.000697

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00281

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00227 AC: 345 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74470

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00197 Hom.: 0

Bravo AF: 0.00250

Asia WGS AF: 0.00173 AC: 6 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 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.7
Dann	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.026
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: rs188447644; hg19: chr4-56325187; COSMIC: COSV59401983; COSMIC: COSV59401983;