4-55449478-G-A

Position:

• chr4-55449478-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004898.4(CLOCK):​c.1367C>T​(p.Pro456Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000395 in 1,613,888 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (6 hom.)
• Consequence: CLOCK NM_004898.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.02

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055678785).
• BP6: Variant 4-55449478-G-A is Benign according to our data. Variant chr4-55449478-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 722817.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.1367C>T	p.Pro456Leu	missense_variant	17/23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.1367C>T	p.Pro456Leu	missense_variant	17/23	1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152076 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000835 AC: 210 AN: 251422 Hom.: 1 AF XY: 0.00105 AC XY: 143 AN XY: 135876

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00627

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000415 AC: 607 AN: 1461694 Hom.: 6 Cov.: 31 AF XY: 0.000580 AC XY: 422 AN XY: 727150

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00565

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000728

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74424

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000947 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000931 AC: 113

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	22
DANN	Benign	0.19
DEOGEN2	Benign	0.054	T;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.67	T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0056	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.24
MVP		0.13
MPC		0.34
ClinPred		0.013	T
GERP RS		3.9
Varity_R		0.024
gMVP		0.20

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: rs578243815; hg19: chr4-56315645; COSMIC: COSV59403588; COSMIC: COSV59403588;