4-55443825-A-G

Variant names:

• chr4-55443825-A-G
• rs3736544
• NM_004898.4:c.1764T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004898.4(CLOCK):​c.1764T>C​(p.Asn588Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,613,442 control chromosomes in the GnomAD database, including 358,738 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 0.69 (36338 hom., cov: 32)
  • Exomes 𝑓: 0.66 (322400 hom.)
• Consequence: CLOCK NM_004898.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.408
• Publications: 55 publications found

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]

TMEM165 Gene-Disease associations (from GenCC):

• TMEM165-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004898.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	NM_004898.4	MANE Select	c.1764T>C	p.Asn588Asn	synonymous	Exon 20 of 23	NP_004889.1
	CLOCK	NM_001267843.2		c.1764T>C	p.Asn588Asn	synonymous	Exon 21 of 24	NP_001254772.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLOCK	ENST00000513440.6	TSL:1 MANE Select	c.1764T>C	p.Asn588Asn	synonymous	Exon 20 of 23	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.1764T>C	p.Asn588Asn	synonymous	Exon 19 of 22	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.1764T>C	p.Asn588Asn	synonymous	Exon 21 of 24	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.689 AC: 104641 AN: 151924 Hom.: 36294 Cov.: 32

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.660

GnomAD2 exomes AF: 0.696 AC: 174793 AN: 251220 AF XY: 0.697

Gnomad AFR exome AF: 0.738

Gnomad AMR exome AF: 0.747

Gnomad ASJ exome AF: 0.661

Gnomad EAS exome AF: 0.679

Gnomad FIN exome AF: 0.746

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.662 AC: 967019 AN: 1461400 Hom.: 322400 Cov.: 49 AF XY: 0.666 AC XY: 484237 AN XY: 727018

African (AFR) AF: 0.742 AC: 24851 AN: 33472

American (AMR) AF: 0.740 AC: 33112 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 17363 AN: 26134

East Asian (EAS) AF: 0.737 AC: 29251 AN: 39692

South Asian (SAS) AF: 0.808 AC: 69720 AN: 86244

European-Finnish (FIN) AF: 0.741 AC: 39567 AN: 53408

Middle Eastern (MID) AF: 0.627 AC: 3565 AN: 5684

European-Non Finnish (NFE) AF: 0.638 AC: 708962 AN: 1111670

Other (OTH) AF: 0.673 AC: 40628 AN: 60376

GnomAD4 genome AF: 0.689 AC: 104730 AN: 152042 Hom.: 36338 Cov.: 32 AF XY: 0.697 AC XY: 51808 AN XY: 74316

African (AFR) AF: 0.732 AC: 30331 AN: 41458

American (AMR) AF: 0.710 AC: 10850 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2275 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3523 AN: 5156

South Asian (SAS) AF: 0.813 AC: 3920 AN: 4822

European-Finnish (FIN) AF: 0.752 AC: 7947 AN: 10564

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43785 AN: 67980

Other (OTH) AF: 0.663 AC: 1400 AN: 2112

Alfa AF: 0.658 Hom.: 33156

Bravo AF: 0.682

Asia WGS AF: 0.758 AC: 2639 AN: 3478

EpiCase AF: 0.639

EpiControl AF: 0.639

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.58
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3736544; hg19: chr4-56309992; COSMIC: COSV59401601; COSMIC: COSV59401601;