chr4-55455999-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004898.4(CLOCK):c.880C>T(p.Pro294Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,756 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CLOCK
NM_004898.4 missense
NM_004898.4 missense
Scores
4
6
9
Clinical Significance
Conservation
PhyloP100: 10.0
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLOCK | NM_004898.4 | c.880C>T | p.Pro294Ser | missense_variant | 13/23 | ENST00000513440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLOCK | ENST00000513440.6 | c.880C>T | p.Pro294Ser | missense_variant | 13/23 | 1 | NM_004898.4 | P1 | |
CLOCK | ENST00000309964.8 | c.880C>T | p.Pro294Ser | missense_variant | 12/22 | 1 | P1 | ||
CLOCK | ENST00000381322.5 | c.880C>T | p.Pro294Ser | missense_variant | 14/24 | 1 | P1 | ||
CLOCK | ENST00000506747.5 | n.1170C>T | non_coding_transcript_exon_variant | 12/13 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000660 AC: 1AN: 151480Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455276Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724264
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GnomAD4 genome ? AF: 0.00000660 AC: 1AN: 151480Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73878
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.880C>T (p.P294S) alteration is located in exon 13 (coding exon 10) of the CLOCK gene. This alteration results from a C to T substitution at nucleotide position 880, causing the proline (P) at amino acid position 294 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;P;P
Vest4
MutPred
Loss of catalytic residue at P294 (P = 5e-04);Loss of catalytic residue at P294 (P = 5e-04);Loss of catalytic residue at P294 (P = 5e-04);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at