NM_001012759.3:c.68G>A

Variant names:

• chr16-88706598-G-A
• rs536176202
• NM_001012759.3:c.68G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012759.3(CTU2):​c.68G>A​(p.Ser23Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,432,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. S23T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CTU2 NM_001012759.3 missense, splice_region
• Scores: Splicing: ADA: 0.9962
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

CTU2 (HGNC:28005): (cytosolic thiouridylase subunit 2) This gene encodes a protein which is involved in the post-transcriptional modification of transfer RNAs (tRNAs). The encoded protein plays a role in thiolation of uridine residue present at the wobble position in a subset of tRNAs, resulting in enhanced codon reading accuracy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

RNF166 (HGNC:28856): (ring finger protein 166) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in protein polyubiquitination and ubiquitin-dependent protein catabolic process. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTU2	NM_001012759.3	c.68G>A	p.Ser23Asn	missense_variant, splice_region_variant	Exon 1 of 15	ENST00000453996.7	NP_001012777.1
RNF166	NM_178841.4	c.-273C>T		upstream_gene_variant		ENST00000312838.9	NP_849163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTU2	ENST00000453996.7	c.68G>A	p.Ser23Asn	missense_variant, splice_region_variant	Exon 1 of 15	1	NM_001012759.3	ENSP00000388320.2
RNF166	ENST00000312838.9	c.-273C>T		upstream_gene_variant		1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152048 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

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

GnomAD2 exomes AF: 0.0000209 AC: 1 AN: 47850 AF XY: 0.0000344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000156 AC: 2 AN: 1280534 Hom.: 0 Cov.: 31 AF XY: 0.00000159 AC XY: 1 AN XY: 630358

African (AFR) AF: 0.00 AC: 0 AN: 25050

American (AMR) AF: 0.00 AC: 0 AN: 17430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21026

East Asian (EAS) AF: 0.0000711 AC: 2 AN: 28134

South Asian (SAS) AF: 0.00 AC: 0 AN: 67134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1033344

Other (OTH) AF: 0.00 AC: 0 AN: 52798

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000319 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.0023	T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PhyloP100		1.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.24	B;B;.
Vest4		0.095
MutPred		0.21		Loss of phosphorylation at S23 (P = 0.0018);Loss of phosphorylation at S23 (P = 0.0018);Loss of phosphorylation at S23 (P = 0.0018);
MVP		0.18
ClinPred		0.14	T
GERP RS		3.2
PromoterAI		0.26	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.096
gMVP		0.31
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.030		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: rs536176202; hg19: chr16-88773006;