16-88707186-T-A

Position:

• chr16-88707186-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001012759.3(CTU2):​c.119T>A​(p.Ile40Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,613,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CTU2 NM_001012759.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.70

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTU2	NM_001012759.3	c.119T>A	p.Ile40Lys	missense_variant	2/15	ENST00000453996.7
CTU2	NM_001318507.2	c.119T>A	p.Ile40Lys	missense_variant	2/15
CTU2	NM_001012762.3	c.119T>A	p.Ile40Lys	missense_variant	2/14
CTU2	NM_001318513.2	c.-64T>A		5_prime_UTR_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTU2	ENST00000453996.7	c.119T>A	p.Ile40Lys	missense_variant	2/15	1	NM_001012759.3	P2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 250926 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135832

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461598 Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125 AN XY: 727076

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

CTU2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2023

The CTU2 c.119T>A variant is predicted to result in the amino acid substitution p.Ile40Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-88773594-T-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 40 of the CTU2 protein (p.Ile40Lys). This variant is present in population databases (rs61730430, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CTU2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.042	T;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.84
MVP		0.63
ClinPred		0.75	D
GERP RS		3.1
Varity_R		0.71
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61730430; hg19: chr16-88773594;