chr16-88706579-C-G

Variant names:

• chr16-88706579-C-G
• rs954349089
• NM_001012759.3:c.49C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012759.3(CTU2):​c.49C>G​(p.Pro17Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,451,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: CTU2 NM_001012759.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.340
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07370731).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTU2	NM_001012759.3	c.49C>G	p.Pro17Ala	missense_variant	Exon 1 of 15	ENST00000453996.7	NP_001012777.1
RNF166	NM_178841.4	c.-254G>C		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.49C>G	p.Pro17Ala	missense_variant	Exon 1 of 15	1	NM_001012759.3	ENSP00000388320.2
RNF166	ENST00000312838.9	c.-254G>C		upstream_gene_variant		1	NM_178841.4	ENSP00000326095.4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151924 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000462 AC: 6 AN: 1299112 Hom.: 0 Cov.: 31 AF XY: 0.00000312 AC XY: 2 AN XY: 640666

African (AFR) AF: 0.00 AC: 0 AN: 25822

American (AMR) AF: 0.00 AC: 0 AN: 22006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22476

East Asian (EAS) AF: 0.00 AC: 0 AN: 28150

South Asian (SAS) AF: 0.00 AC: 0 AN: 70234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3848

European-Non Finnish (NFE) AF: 0.00000577 AC: 6 AN: 1040414

Other (OTH) AF: 0.00 AC: 0 AN: 53700

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151924 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74212

African (AFR) AF: 0.0000242 AC: 1 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.49C>G (p.P17A) alteration is located in exon 1 (coding exon 1) of the CTU2 gene. This alteration results from a C to G substitution at nucleotide position 49, causing the proline (P) at amino acid position 17 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.1
DANN	Benign	0.44
DEOGEN2	Benign	0.022	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.000090	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M;.
PhyloP100		-0.34
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.024	B;B;.
Vest4		0.15
MutPred		0.23		Loss of glycosylation at P17 (P = 0.0031);Loss of glycosylation at P17 (P = 0.0031);Loss of glycosylation at P17 (P = 0.0031);
MVP		0.088
ClinPred		0.097	T
GERP RS		2.1
PromoterAI		-0.0065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.034
gMVP		0.29
Mutation Taster		=95/5	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: rs954349089; hg19: chr16-88772987;