18-57436420-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_004852.3(ONECUT2):c.704G>T(p.Gly235Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
ONECUT2
NM_004852.3 missense
NM_004852.3 missense
Scores
5
10
2
Clinical Significance
Conservation
PhyloP100: 9.58
Genes affected
ONECUT2 (HGNC:8139): (one cut homeobox 2) This gene encodes a member of the onecut family of transcription factors, which are characterized by a cut domain and an atypical homeodomain. The protein binds to specific DNA sequences and stimulates expression of target genes, including genes involved in melanocyte and hepatocyte differentiation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.843
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ONECUT2 | NM_004852.3 | c.704G>T | p.Gly235Val | missense_variant | 1/2 | ENST00000491143.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ONECUT2 | ENST00000491143.3 | c.704G>T | p.Gly235Val | missense_variant | 1/2 | 1 | NM_004852.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459498Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 726202
GnomAD4 exome
AF:
AC:
1
AN:
1459498
Hom.:
Cov.:
35
AF XY:
AC XY:
1
AN XY:
726202
Gnomad4 AFR exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
Asia WGS
AF:
AC:
1
AN:
3478
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 | Jul 25, 2023 | The c.704G>T (p.G235V) alteration is located in exon 1 (coding exon 1) of the ONECUT2 gene. This alteration results from a G to T substitution at nucleotide position 704, causing the glycine (G) at amino acid position 235 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
REVEL
Uncertain
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at P231 (P = 0.0914);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at