dbSNP rs1315311088: ONECUT2:p.His57Pro (chr18-57435886-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004852.3(ONECUT2):c.170A>C(p.His57Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 145,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H57R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ONECUT2
NM_004852.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.37

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087240696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3 link	c.170A>C	p.His57Pro	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.170A>C	p.His57Pro	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2		O95948

Frequencies

GnomAD3 genomes

AF:

0.0000138

AC:

AN:

145222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000495

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000212

AC:

AN:

944498

Hom.:

Cov.:

AF XY:

0.00000449

AC XY:

AN XY:

445288

show subpopulations

African (AFR)

AF:

0.0000545

AC:

AN:

18338

American (AMR)

AF:

0.00

AC:

AN:

4034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8336

East Asian (EAS)

AF:

0.00

AC:

AN:

11236

South Asian (SAS)

AF:

0.00

AC:

AN:

18386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

13620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2156

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

834596

Other (OTH)

AF:

0.0000296

AC:

AN:

33796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000138

AC:

AN:

145222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70572

show subpopulations

African (AFR)

AF:

0.0000495

AC:

AN:

40394

American (AMR)

AF:

0.00

AC:

AN:

14686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3384

East Asian (EAS)

AF:

0.00

AC:

AN:

4936

South Asian (SAS)

AF:

0.00

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65498

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.11

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.32

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.29

PhyloP100

1.4

PrimateAI

Uncertain

0.77

REVEL

Benign

0.064

Sift4G

Benign

0.084

Polyphen

0.0

Vest4

0.10

MutPred

0.13

Gain of glycosylation at H57 (P = 0.0205);

MVP

0.18

MPC

1.1

ClinPred

0.027

GERP RS

1.9

Varity_R

0.18

gMVP

0.19

Mutation Taster

=84/16

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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rs1315311088

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over