Genetic Variant ONECUT2:p.Glu60Lys (chr18-57435894-G-A) – 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.178G>A(p.Glu60Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,111,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ONECUT2
NM_004852.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.86

Publications

1 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=0.102891).

BS2

High AC in GnomAd4 at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3 link	c.178G>A	p.Glu60Lys	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.178G>A	p.Glu60Lys	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2		O95948

Frequencies

GnomAD3 genomes

AF:

0.000295

AC:

AN:

145796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000493

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000503

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000187

AC:

181

AN:

965840

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

103

AN XY:

455514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18962

American (AMR)

AF:

0.00

AC:

AN:

4656

Ashkenazi Jewish (ASJ)

AF:

0.000327

AC:

AN:

9186

East Asian (EAS)

AF:

0.00

AC:

AN:

13522

South Asian (SAS)

AF:

0.00

AC:

AN:

18596

European-Finnish (FIN)

AF:

0.000597

AC:

AN:

15080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2274

European-Non Finnish (NFE)

AF:

0.000195

AC:

165

AN:

848236

Other (OTH)

AF:

0.000113

AC:

AN:

35328

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:

0.000295

AC:

AN:

145796

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

70852

show subpopulations

African (AFR)

AF:

0.0000493

AC:

AN:

40584

American (AMR)

AF:

0.00

AC:

AN:

14712

Ashkenazi Jewish (ASJ)

AF:

0.00118

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4992

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

8498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.000503

AC:

AN:

65636

Other (OTH)

AF:

0.00

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000702

Hom.:

Bravo

AF:

0.000246

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.178G>A (p.E60K) alteration is located in exon 1 (coding exon 1) of the ONECUT2 gene. This alteration results from a G to A substitution at nucleotide position 178, causing the glutamic acid (E) at amino acid position 60 to be replaced by a lysine (K). 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.54

M_CAP

Benign

0.039

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

1.9

PrimateAI

Pathogenic

0.84

REVEL

Benign

0.10

Sift4G

Benign

0.25

Polyphen

0.20

Vest4

0.12

MVP

0.40

MPC

0.80

ClinPred

0.53

GERP RS

2.2

Varity_R

0.17

gMVP

0.34

Mutation Taster

=91/9

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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18-57435894-G-A

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