chr4-55459020-T-C
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2
The NM_004898.4(CLOCK):c.674-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,594,972 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).
Frequency
Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 13 hom. )
Consequence
CLOCK
NM_004898.4 splice_polypyrimidine_tract, intron
NM_004898.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00001503
2
Clinical Significance
Conservation
PhyloP100: -1.87
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 Benign. Variant got -14 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 4-55459020-T-C is Benign according to our data. Variant chr4-55459020-T-C is described in ClinVar as [Benign]. Clinvar id is 720262.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00159 (2288/1442672) while in subpopulation MID AF= 0.0223 (128/5734). AF 95% confidence interval is 0.0192. There are 13 homozygotes in gnomad4_exome. There are 1263 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.
BS2
?
High AC in GnomAd at 344 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLOCK | NM_004898.4 | c.674-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000513440.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLOCK | ENST00000513440.6 | c.674-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_004898.4 | P1 | |||
CLOCK | ENST00000309964.8 | c.674-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | P1 | ||||
CLOCK | ENST00000381322.5 | c.674-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | P1 | ||||
CLOCK | ENST00000506747.5 | n.964-10A>G | splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00226 AC: 344AN: 152182Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00245 AC: 614AN: 251124Hom.: 3 AF XY: 0.00265 AC XY: 359AN XY: 135696
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GnomAD4 exome AF: 0.00159 AC: 2288AN: 1442672Hom.: 13 Cov.: 27 AF XY: 0.00176 AC XY: 1263AN XY: 718990
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ClinVar
Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at