4-55453077-G-T

Position:

• chr4-55453077-G-T

Variant summary

Our verdict is Benign. Variant got -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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1183C>A	p.Leu395Ile	missense_variant	15/23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.1183C>A	p.Leu395Ile	missense_variant	15/23	1	NM_004898.4	ENSP00000426983.1
CLOCK	ENST00000309964.8	c.1183C>A	p.Leu395Ile	missense_variant	14/22	1		ENSP00000308741.4
CLOCK	ENST00000381322.5	c.1183C>A	p.Leu395Ile	missense_variant	16/24	1		ENSP00000370723.1
TMEM165	ENST00000608091.1	c.*771G>T		3_prime_UTR_variant	4/4	3		ENSP00000476531.1

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

GnomAD3 exomes AF: 0.0204 AC: 5131 AN: 251080 Hom.: 642 AF XY: 0.0149 AC XY: 2028 AN XY: 135704

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 SAS exome AF: 0.000555

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

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.0146

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000721

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000625

Gnomad4 OTH exome AF: 0.0183

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

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.0591

Alfa AF: 0.0122 Hom.: 373

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 v4.3

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;T;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;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.24	B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs6855837; hg19: chr4-56319244; COSMIC: COSV104401548; COSMIC: COSV104401548;