rs1048004

Variant names:

• chr4-55434042-C-A
• rs1048004
• ENST00000511124.1:n.2366G>T

Variant summary

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

The ENST00000511124.1(CLOCK):​n.2366G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,430 control chromosomes in the GnomAD database, including 4,976 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 0.25 (4953 hom., cov: 32)
  • Exomes 𝑓: 0.34 (23 hom.)
• Consequence: CLOCK ENST00000511124.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• Publications: 16 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*1373G>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.*1373G>T		3_prime_UTR_variant	Exon 23 of 23	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37437 AN: 151882 Hom.: 4947 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.247

GnomAD4 exome AF: 0.344 AC: 148 AN: 430 Hom.: 23 Cov.: 0 AF XY: 0.368 AC XY: 95 AN XY: 258

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) AF: 0.344 AC: 146 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 1 AN: 2

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.246 AC: 37462 AN: 152000 Hom.: 4953 Cov.: 32 AF XY: 0.251 AC XY: 18685 AN XY: 74304

African (AFR) AF: 0.172 AC: 7140 AN: 41488

American (AMR) AF: 0.234 AC: 3561 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 820 AN: 3468

East Asian (EAS) AF: 0.0998 AC: 517 AN: 5178

South Asian (SAS) AF: 0.372 AC: 1787 AN: 4806

European-Finnish (FIN) AF: 0.356 AC: 3760 AN: 10550

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19039 AN: 67946

Other (OTH) AF: 0.245 AC: 517 AN: 2108

Alfa AF: 0.263 Hom.: 3222

Bravo AF: 0.226

Asia WGS AF: 0.260 AC: 907 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.7
DANN	Benign	0.60
PhyloP100		-2.2
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: rs1048004; hg19: chr4-56300209; COSMIC: COSV59400294; COSMIC: COSV59400294;