18-57435831-G-C

Variant names:

• chr18-57435831-G-C
• rs775311962
• NM_004852.3:c.115G>C

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.115G>C​(p.Gly39Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000316 in 950,454 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. G39D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.241
• 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=0.090054065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.115G>C	p.Gly39Arg	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.115G>C	p.Gly39Arg	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000316 AC: 3 AN: 950454 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 456738

African (AFR) AF: 0.00 AC: 0 AN: 17956

American (AMR) AF: 0.00 AC: 0 AN: 10294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9272

East Asian (EAS) AF: 0.00 AC: 0 AN: 7600

South Asian (SAS) AF: 0.00 AC: 0 AN: 30640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1978

European-Non Finnish (NFE) AF: 0.00000365 AC: 3 AN: 821990

Other (OTH) AF: 0.00 AC: 0 AN: 31380

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.24
PrimateAI	Pathogenic	0.85	D
REVEL	Benign	0.057
Sift4G	Benign	0.17	T
Polyphen		0.21	B
Vest4		0.23
MutPred		0.16		Gain of methylation at G39 (P = 0.0183);
MVP		0.32
MPC		0.89
ClinPred		0.14	T
GERP RS		0.75
PromoterAI		0.0068	Neutral
Varity_R		0.080
gMVP		0.20
Mutation Taster		=97/3	polymorphism

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: rs775311962; hg19: chr18-55103063;