18-57435846-G-T

Variant names:

• chr18-57435846-G-T
• rs201085296
• NM_004852.3:c.130G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004852.3(ONECUT2):​c.130G>T​(p.Gly44Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000117 in 857,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G44S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480
• 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: 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=0.2323693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.130G>T	p.Gly44Cys	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.130G>T	p.Gly44Cys	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000117 AC: 1 AN: 857216 Hom.: 0 Cov.: 31 AF XY: 0.00000250 AC XY: 1 AN XY: 400406

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

African (AFR) AF: 0.00 AC: 0 AN: 15978

American (AMR) AF: 0.00 AC: 0 AN: 1326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4138

South Asian (SAS) AF: 0.00 AC: 0 AN: 17586

European-Finnish (FIN) AF: 0.000129 AC: 1 AN: 7744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775346

Other (OTH) AF: 0.00 AC: 0 AN: 28096

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.43	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.048
PrimateAI	Pathogenic	0.84	D
REVEL	Benign	0.13
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.33		Loss of catalytic residue at G45 (P = 0.4215);
MVP		0.57
MPC		1.8
ClinPred		0.70	D
GERP RS		1.9
PromoterAI		-0.013	Neutral
Varity_R		0.21
gMVP		0.55

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: rs201085296; hg19: chr18-55103078;