rs2412646

Positions:

• chr4-55452605-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.1206+449A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 172,352 control chromosomes in the GnomAD database, including 31,980 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 0.58 (27591 hom., cov: 32)
  • Exomes 𝑓: 0.65 (4389 hom.)
• Consequence: CLOCK NM_004898.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.40

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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1206+449A>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.1206+449A>G		intron_variant		1	NM_004898.4	ENSP00000426983	P1
CLOCK	ENST00000309964.8	c.1206+449A>G		intron_variant		1		ENSP00000308741	P1
CLOCK	ENST00000381322.5	c.1206+449A>G		intron_variant		1		ENSP00000370723	P1
TMEM165	ENST00000608091.1	c.*299T>C		3_prime_UTR_variant	4/4	3		ENSP00000476531

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88835 AN: 151890 Hom.: 27570 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.809

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.643

Gnomad OTH AF: 0.582

GnomAD4 exome AF: 0.647 AC: 13170 AN: 20342 Hom.: 4389 Cov.: 0 AF XY: 0.654 AC XY: 7443 AN XY: 11378

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.688

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.694

Gnomad4 SAS exome AF: 0.787

Gnomad4 FIN exome AF: 0.686

Gnomad4 NFE exome AF: 0.612

Gnomad4 OTH exome AF: 0.595

GnomAD4 genome AF: 0.585 AC: 88870 AN: 152010 Hom.: 27591 Cov.: 32 AF XY: 0.597 AC XY: 44381 AN XY: 74316

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.654

Gnomad4 EAS AF: 0.684

Gnomad4 SAS AF: 0.810

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.643

Gnomad4 OTH AF: 0.586

Alfa AF: 0.618 Hom.: 3740

Bravo AF: 0.563

Asia WGS AF: 0.736 AC: 2560 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.16
DANN	Benign	0.45

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: rs2412646; hg19: chr4-56318772;