18-57435890-G-T

Variant names:

• chr18-57435890-G-T
• rs1232029502
• NM_004852.3:c.174G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004852.3(ONECUT2):​c.174G>T​(p.Glu58Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E58A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06204045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.174G>T	p.Glu58Asp	missense_variant	Exon 1 of 2	ENST00000491143.3	NP_004843.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT2	ENST00000491143.3	c.174G>T	p.Glu58Asp	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.174G>T (p.E58D) 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 174, causing the glutamic acid (E) at amino acid position 58 to be replaced by an aspartic acid (D). 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	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.80	T
REVEL	Benign	0.10
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.15		Loss of glycosylation at P55 (P = 0.1483);
MVP		0.15
MPC		0.62
ClinPred		0.68	D
GERP RS		1.2
Varity_R		0.086
gMVP		0.11
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs1232029502; hg19: chr18-55103122;