ENST00000511124.1:n.1220A>G

Variant names:

• chr4-55435188-T-C
• rs70965446
• ENST00000511124.1:n.1220A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000511124.1(CLOCK):​n.1220A>G 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 0.00182 in 559,472 control chromosomes in the GnomAD database, including 6 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 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: CLOCK ENST00000511124.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.58
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BS2: High AC in GnomAd4 at 204 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*227A>G		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.*227A>G		3_prime_UTR_variant	Exon 23 of 23	1	NM_004898.4	ENSP00000426983.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00199 AC: 812 AN: 407158 Hom.: 6 Cov.: 4 AF XY: 0.00218 AC XY: 466 AN XY: 214184

African (AFR) AF: 0.000173 AC: 2 AN: 11540

American (AMR) AF: 0.0000586 AC: 1 AN: 17060

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 19 AN: 12302

East Asian (EAS) AF: 0.00 AC: 0 AN: 27412

South Asian (SAS) AF: 0.00406 AC: 178 AN: 43806

European-Finnish (FIN) AF: 0.00304 AC: 82 AN: 27008

Middle Eastern (MID) AF: 0.00349 AC: 6 AN: 1720

European-Non Finnish (NFE) AF: 0.00194 AC: 471 AN: 242860

Other (OTH) AF: 0.00226 AC: 53 AN: 23450

GnomAD4 genome AF: 0.00134 AC: 204 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74488

African (AFR) AF: 0.000144 AC: 6 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00213 AC: 145 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00312 Hom.: 2

Bravo AF: 0.000892

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs70965446; hg19: chr4-56301355;