4-55453077-G-T

Variant names:

• chr4-55453077-G-T
• rs6855837
• NM_004898.4:c.1183C>A

Variant summary

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

The NM_004898.4(CLOCK):​c.1183C>A​(p.Leu395Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0146 in 1,611,712 control chromosomes in the GnomAD database, including 2,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L395V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.076 (1477 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (1448 hom.)
• Consequence: CLOCK NM_004898.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.38
• 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 (MetaRNN=0.0012733638).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 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.1183C>A	p.Leu395Ile	missense	Exon 15 of 23	NP_004889.1
	CLOCK	NM_001267843.2		c.1183C>A	p.Leu395Ile	missense	Exon 16 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.1183C>A	p.Leu395Ile	missense	Exon 15 of 23	ENSP00000426983.1
	CLOCK	ENST00000309964.8	TSL:1	c.1183C>A	p.Leu395Ile	missense	Exon 14 of 22	ENSP00000308741.4
	CLOCK	ENST00000381322.5	TSL:1	c.1183C>A	p.Leu395Ile	missense	Exon 16 of 24	ENSP00000370723.1

Frequencies

GnomAD3 genomes AF: 0.0757 AC: 11510 AN: 152034 Hom.: 1469 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0598

GnomAD2 exomes AF: 0.0204 AC: 5131 AN: 251080 AF XY: 0.0149

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00824 AC: 12025 AN: 1459560 Hom.: 1448 Cov.: 30 AF XY: 0.00719 AC XY: 5220 AN XY: 726182

African (AFR) AF: 0.282 AC: 9401 AN: 33392

American (AMR) AF: 0.0146 AC: 652 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.000721 AC: 62 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5756

European-Non Finnish (NFE) AF: 0.000625 AC: 694 AN: 1110496

Other (OTH) AF: 0.0183 AC: 1106 AN: 60278

GnomAD4 genome AF: 0.0760 AC: 11561 AN: 152152 Hom.: 1477 Cov.: 32 AF XY: 0.0726 AC XY: 5405 AN XY: 74412

African (AFR) AF: 0.264 AC: 10923 AN: 41434

American (AMR) AF: 0.0271 AC: 414 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68012

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0308 Hom.: 1451

Bravo AF: 0.0871

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.251 AC: 1105

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.0249 AC: 3021

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		4.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.085
Sift	Benign	0.42	T
Sift4G	Benign	0.50	T
Polyphen		0.24	B
Vest4		0.13
MPC		0.45
ClinPred		0.011	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.12
Mutation Taster		=99/1	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: rs6855837; hg19: chr4-56319244; COSMIC: COSV104401548;