18-57435816-G-C

Variant names:

• chr18-57435816-G-C
• rs778121953
• NM_004852.3:c.100G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004852.3(ONECUT2):​c.100G>C​(p.Gly34Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000406 in 984,476 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. G34W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ONECUT2 NM_004852.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30655468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ONECUT2	NM_004852.3	c.100G>C	p.Gly34Arg	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.100G>C	p.Gly34Arg	missense_variant	Exon 1 of 2	1	NM_004852.3	ENSP00000419185.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000406 AC: 4 AN: 984476 Hom.: 0 Cov.: 32 AF XY: 0.00000629 AC XY: 3 AN XY: 476944

African (AFR) AF: 0.00 AC: 0 AN: 18906

American (AMR) AF: 0.00 AC: 0 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10572

East Asian (EAS) AF: 0.00 AC: 0 AN: 8562

South Asian (SAS) AF: 0.00 AC: 0 AN: 34664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2308

European-Non Finnish (NFE) AF: 0.00000476 AC: 4 AN: 839678

Other (OTH) AF: 0.00 AC: 0 AN: 32900

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.080	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.35
MutPred		0.30		Loss of glycosylation at T31 (P = 0.066);
MVP		0.47
MPC		1.9
ClinPred		0.82	D
GERP RS		1.9
PromoterAI		0.0068	Neutral
Varity_R		0.26
gMVP		0.37
Mutation Taster		=77/23	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: rs778121953; hg19: chr18-55103048;