Genetic Variant ONECUT2:p.Gly54Val (chr18-57435877-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004852.3(ONECUT2):c.161G>T(p.Gly54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000276 in 1,050,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000021 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ONECUT2
NM_004852.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.459

Publications

0 publications found

Variant links:

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]

ONECUT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09692049).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3 link	c.161G>T	p.Gly54Val	missense_variant	Exon 1 of 2	ENST00000491143.3	NP_004843.2	O95948

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT2	ENST00000491143.3 link	c.161G>T	p.Gly54Val	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2		O95948

Frequencies

GnomAD3 genomes

AF:

0.0000206

AC:

AN:

145588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000457

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

905062

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

425464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17334

American (AMR)

AF:

0.00

AC:

AN:

2960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6852

East Asian (EAS)

AF:

0.00

AC:

AN:

7502

South Asian (SAS)

AF:

0.00

AC:

AN:

18028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1932

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

808658

Other (OTH)

AF:

0.0000640

AC:

AN:

31274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000206

AC:

AN:

145588

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

70772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40604

American (AMR)

AF:

0.00

AC:

AN:

14682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3378

East Asian (EAS)

AF:

0.00

AC:

AN:

4992

South Asian (SAS)

AF:

0.00

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000457

AC:

AN:

65576

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.161G>T (p.G54V) 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 161, causing the glycine (G) at amino acid position 54 to be replaced by a valine (V). 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

0.082

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.12

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.45

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.46

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.52

REVEL

Benign

0.062

Sift

Benign

0.31

Sift4G

Benign

0.095

Polyphen

0.053

Vest4

0.22

MutPred

0.17

Loss of glycosylation at P55 (P = 0.0725);

MVP

0.28

MPC

0.87

ClinPred

0.072

GERP RS

1.0

Varity_R

0.085

gMVP

0.35

Mutation Taster

=90/10

polymorphism

(source)

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

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18-57435877-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over