4-55442520-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004898.4(CLOCK):c.2017G>A(p.Gly673Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 1,608,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CLOCK NM_004898.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.88

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09729931).
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLOCK	NM_004898.4	c.2017G>A	p.Gly673Arg	missense_variant	21/23	ENST00000513440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLOCK	ENST00000513440.6	c.2017G>A	p.Gly673Arg	missense_variant	21/23	1	NM_004898.4	P1

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 34 AN: 146902 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000100

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000313

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251298 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135812

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 727210

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000231 AC: 34 AN: 147020 Hom.: 0 Cov.: 27 AF XY: 0.000126 AC XY: 9 AN XY: 71326

Gnomad4 AFR AF: 0.000278

Gnomad4 AMR AF: 0.0000692

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000100

Gnomad4 NFE AF: 0.000313

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000317 Hom.: 0

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.2017G>A (p.G673R) alteration is located in exon 21 (coding exon 18) of the CLOCK gene. This alteration results from a G to A substitution at nucleotide position 2017, causing the glycine (G) at amino acid position 673 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.049	T;T;T
Eigen	Benign	0.080
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D;.;.
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.62	T;T;T
Polyphen		0.55	P;P;P
Vest4		0.52
MutPred		0.18		Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);Gain of MoRF binding (P = 0.0256);
MVP		0.17
MPC		0.93
ClinPred		0.047	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.47

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: rs145873359; hg19: chr4-56308687; COSMIC: COSV59401488;