Genetic Variant ONECUT2:c.*13857G>T (chr18-57490580-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004852.3(ONECUT2):c.*13857G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,868 control chromosomes in the GnomAD database, including 11,538 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 11538 hom., cov: 31)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

ONECUT2
NM_004852.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.243

Publications

5 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3 link	c.*13857G>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000491143.3	NP_004843.2	O95948
ONECUT2	XM_047437947.1 link	c.*14068G>T		3_prime_UTR_variant	Exon 3 of 3		XP_047293903.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ONECUT2	ENST00000491143.3 link	c.*13857G>T		3_prime_UTR_variant	Exon 2 of 2	1	NM_004852.3	ENSP00000419185.2		O95948

Frequencies

GnomAD3 genomes

AF:

0.381

AC:

57865

AN:

151746

Hom.:

11504

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.335

Gnomad AMR

AF:

0.462

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.480

Gnomad SAS

AF:

0.404

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.310

Gnomad OTH

AF:

0.387

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.382

AC:

57950

AN:

151864

Hom.:

11538

Cov.:

AF XY:

0.390

AC XY:

28944

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.460

AC:

19055

AN:

41416

American (AMR)

AF:

0.463

AC:

7051

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

1004

AN:

3464

East Asian (EAS)

AF:

0.481

AC:

2481

AN:

5158

South Asian (SAS)

AF:

0.406

AC:

1951

AN:

4810

European-Finnish (FIN)

AF:

0.392

AC:

4128

AN:

10532

Middle Eastern (MID)

AF:

0.363

AC:

106

AN:

292

European-Non Finnish (NFE)

AF:

0.310

AC:

21053

AN:

67926

Other (OTH)

AF:

0.386

AC:

816

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1769

3538

5306

7075

8844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

564

1128

1692

2256

2820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.320

Hom.:

3696

Bravo

AF:

0.392

Asia WGS

AF:

0.422

AC:

1466

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.2

(source)

DANN

Benign

0.62

PhyloP100

-0.24

Mutation Taster

=100/0

polymorphism (auto)

(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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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