rs10462028

Positions:

• chr4-55432133-G-A

Variant summary

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

The ENST00000513440.6(CLOCK):​c.*3282C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 152,014 control chromosomes in the GnomAD database, including 6,463 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 0.28 (6463 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLOCK ENST00000513440.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690

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]

TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*3282C>T		3_prime_UTR_variant	23/23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.*3282C>T		3_prime_UTR_variant	23/23	1	NM_004898.4	ENSP00000426983	P1
CLOCK	ENST00000309964.8	c.*3282C>T		3_prime_UTR_variant	22/22	1		ENSP00000308741	P1
TMEM165	ENST00000608091.1	c.408+7490G>A		intron_variant		3		ENSP00000476531
TMEM165	ENST00000506103.2	c.*270+7490G>A		intron_variant, NMD_transcript_variant		3		ENSP00000476621

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42561 AN: 151896 Hom.: 6455 Cov.: 33

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.397

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.270

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.280 AC: 42586 AN: 152014 Hom.: 6463 Cov.: 33 AF XY: 0.284 AC XY: 21130 AN XY: 74300

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.399

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.268

Alfa AF: 0.310 Hom.: 2424

Bravo AF: 0.258

Asia WGS AF: 0.268 AC: 933 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.9
DANN	Benign	0.58

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: rs10462028; hg19: chr4-56298300;