16-88706555-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001012759.3(CTU2):c.25G>A(p.Gly9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,458,604 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 33)
  • Exomes 𝑓: 0.019 (250 hom.)
• Consequence: CTU2 NM_001012759.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.792

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023970008).
• BP6: Variant 16-88706555-G-A is Benign according to our data. Variant chr16-88706555-G-A is described in ClinVar as [Benign]. Clinvar id is 1529311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0135 (2054/152140) while in subpopulation NFE AF= 0.0215 (1458/67950). AF 95% confidence interval is 0.0205. There are 22 homozygotes in gnomad4. There are 949 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTU2	NM_001012759.3	c.25G>A	p.Gly9Arg	missense_variant	1/15	ENST00000453996.7
CTU2	NM_001318507.2	c.25G>A	p.Gly9Arg	missense_variant	1/15
CTU2	NM_001012762.3	c.25G>A	p.Gly9Arg	missense_variant	1/14
CTU2	NM_001318513.2	c.-158G>A		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTU2	ENST00000453996.7	c.25G>A	p.Gly9Arg	missense_variant	1/15	1	NM_001012759.3	P2

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2055 AN: 152032 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.00802

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0152 AC: 1069 AN: 70398 Hom.: 13 AF XY: 0.0156 AC XY: 642 AN XY: 41208

Gnomad AFR exome AF: 0.00229

Gnomad AMR exome AF: 0.00772

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0211

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0186 AC: 24330 AN: 1306464 Hom.: 250 Cov.: 31 AF XY: 0.0184 AC XY: 11835 AN XY: 644460

Gnomad4 AFR exome AF: 0.00241

Gnomad4 AMR exome AF: 0.00960

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0000355

Gnomad4 SAS exome AF: 0.00938

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0135 AC: 2054 AN: 152140 Hom.: 22 Cov.: 33 AF XY: 0.0128 AC XY: 949 AN XY: 74398

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00802

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00869 Hom.: 0

Bravo AF: 0.0134

ESP6500AA AF: 0.00182 AC: 5

ESP6500EA AF: 0.0127 AC: 73

ExAC AF: 0.00614 AC: 427

Asia WGS AF: 0.00232 AC: 9 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CTU2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.0053	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00018	N
LIST_S2	Benign	0.67	T;T;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.41	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.015
MutPred		0.10		Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);Loss of relative solvent accessibility (P = 0.0676);
ClinPred		0.0044	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs137933845; hg19: chr16-88772963; COSMIC: COSV100371892; COSMIC: COSV100371892;