rs6811520

Positions:

• chr4-55449011-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.1450-143A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 683,606 control chromosomes in the GnomAD database, including 164,981 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 0.72 (39732 hom., cov: 31)
  • Exomes 𝑓: 0.68 (125249 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1450-143A>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.1450-143A>G		intron_variant		1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 108955 AN: 151854 Hom.: 39661 Cov.: 31

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.682 AC: 362644 AN: 531632 Hom.: 125249 AF XY: 0.687 AC XY: 194492 AN XY: 283134

Gnomad4 AFR exome AF: 0.834

Gnomad4 AMR exome AF: 0.736

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.747

Gnomad4 SAS exome AF: 0.806

Gnomad4 FIN exome AF: 0.737

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.678

GnomAD4 genome AF: 0.718 AC: 109083 AN: 151974 Hom.: 39732 Cov.: 31 AF XY: 0.725 AC XY: 53806 AN XY: 74256

Gnomad4 AFR AF: 0.833

Gnomad4 AMR AF: 0.720

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.684

Gnomad4 SAS AF: 0.814

Gnomad4 FIN AF: 0.750

Gnomad4 NFE AF: 0.644

Gnomad4 OTH AF: 0.684

Alfa AF: 0.673 Hom.: 15825

Bravo AF: 0.715

Asia WGS AF: 0.769 AC: 2676 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.44

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: rs6811520; hg19: chr4-56315178; COSMIC: COSV59400764; COSMIC: COSV59400764;