rs6832769

Variant names:

• chr4-55432027-G-A
• rs6832769
• NM_004898.4:c.*3388C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.*3388C>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 0.684 in 152,028 control chromosomes in the GnomAD database, including 35,852 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 0.68 (35851 hom., cov: 32)
  • Exomes 𝑓: 0.58 (1 hom.)
• Consequence: CLOCK NM_004898.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*3388C>T		3_prime_UTR_variant	Exon 23 of 23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.*3388C>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.*3388C>T		3_prime_UTR_variant	Exon 22 of 22	1		ENSP00000308741.4
TMEM165	ENST00000608091.1	c.406+7384G>A		intron_variant	Intron 3 of 3	3		ENSP00000476531.1
TMEM165	ENST00000506103.2	n.*270+7384G>A		intron_variant	Intron 2 of 2	3		ENSP00000476621.1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 103963 AN: 151898 Hom.: 35808 Cov.: 32

Gnomad AFR AF: 0.716

Gnomad AMI AF: 0.578

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.812

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.659

GnomAD4 exome AF: 0.583 AC: 7 AN: 12 Hom.: 1 Cov.: 0 AF XY: 0.600 AC XY: 6 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.583 AC: 7 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.684 AC: 104051 AN: 152016 Hom.: 35851 Cov.: 32 AF XY: 0.693 AC XY: 51457 AN XY: 74288

African (AFR) AF: 0.716 AC: 29699 AN: 41466

American (AMR) AF: 0.708 AC: 10824 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2274 AN: 3470

East Asian (EAS) AF: 0.684 AC: 3540 AN: 5174

South Asian (SAS) AF: 0.813 AC: 3917 AN: 4820

European-Finnish (FIN) AF: 0.752 AC: 7927 AN: 10546

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

European-Non Finnish (NFE) AF: 0.644 AC: 43776 AN: 67948

Other (OTH) AF: 0.662 AC: 1395 AN: 2108

Alfa AF: 0.657 Hom.: 61750

Bravo AF: 0.677

Asia WGS AF: 0.758 AC: 2636 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.094
DANN	Benign	0.39
PhyloP100		-1.2
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: rs6832769; hg19: chr4-56298194;