4-55470874-T-C

Position:

• chr4-55470874-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.349-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,096,044 control chromosomes in the GnomAD database, including 82,694 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 0.34 (9374 hom., cov: 32)
  • Exomes 𝑓: 0.39 (73320 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.704

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 (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.349-68A>G		intron_variant		ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.349-68A>G		intron_variant		1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51373 AN: 151892 Hom.: 9365 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.388 AC: 365854 AN: 944034 Hom.: 73320 AF XY: 0.389 AC XY: 190842 AN XY: 490550

Gnomad4 AFR exome AF: 0.190

Gnomad4 AMR exome AF: 0.504

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.610

Gnomad4 SAS exome AF: 0.445

Gnomad4 FIN exome AF: 0.401

Gnomad4 NFE exome AF: 0.367

Gnomad4 OTH exome AF: 0.386

GnomAD4 genome AF: 0.338 AC: 51382 AN: 152010 Hom.: 9374 Cov.: 32 AF XY: 0.345 AC XY: 25651 AN XY: 74276

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.439

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.342

Alfa AF: 0.352 Hom.: 2572

Bravo AF: 0.337

Asia WGS AF: 0.474 AC: 1647 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.87

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: rs3805151; hg19: chr4-56337041;