rs137933845

Variant names:

• chr16-88706555-G-A
• rs137933845
• NM_001012759.3:c.25G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88706555-G-A
• chr16-88706555-G-C
• chr16-88706555-G-T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9E) has been classified as Uncertain significance.

• 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:3
• Conservation: PhyloP100: -0.792
• Publications: 5 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012759.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTU2	NM_001012759.3	MANE Select	c.25G>A	p.Gly9Arg	missense	Exon 1 of 15	NP_001012777.1	Q2VPK5-1
	CTU2	NM_001318507.2		c.25G>A	p.Gly9Arg	missense	Exon 1 of 15	NP_001305436.1	H3BSW6
	CTU2	NM_001012762.3		c.25G>A	p.Gly9Arg	missense	Exon 1 of 14	NP_001012780.1	Q2VPK5-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTU2	ENST00000453996.7	TSL:1 MANE Select	c.25G>A	p.Gly9Arg	missense	Exon 1 of 15	ENSP00000388320.2	Q2VPK5-1
	CTU2	ENST00000567949.5	TSL:1	c.25G>A	p.Gly9Arg	missense	Exon 1 of 15	ENSP00000456908.1	H3BSW6
	CTU2	ENST00000564105.5	TSL:1	n.25G>A		non_coding_transcript_exon	Exon 1 of 14	ENSP00000454923.1	H3BNM3

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

GnomAD2 exomes AF: 0.0152 AC: 1069 AN: 70398 AF XY: 0.0156

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 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

African (AFR) AF: 0.00241 AC: 63 AN: 26130

American (AMR) AF: 0.00960 AC: 223 AN: 23238

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 518 AN: 22788

East Asian (EAS) AF: 0.0000355 AC: 1 AN: 28144

South Asian (SAS) AF: 0.00938 AC: 669 AN: 71350

European-Finnish (FIN) AF: 0.0112 AC: 367 AN: 32688

Middle Eastern (MID) AF: 0.0224 AC: 88 AN: 3922

European-Non Finnish (NFE) AF: 0.0206 AC: 21476 AN: 1044164

Other (OTH) AF: 0.0171 AC: 925 AN: 54040

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

African (AFR) AF: 0.00327 AC: 136 AN: 41538

American (AMR) AF: 0.0133 AC: 204 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4826

European-Finnish (FIN) AF: 0.00802 AC: 85 AN: 10602

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0215 AC: 1458 AN: 67950

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.0135 Hom.: 3

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CTU2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		-0.79
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.031
Sift	Benign	0.41	T
Sift4G	Benign	0.14	T
Polyphen		0.0060	B
Vest4		0.015
MutPred		0.10		Loss of relative solvent accessibility (P = 0.0676)
ClinPred		0.0044	T
GERP RS		1.1
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.29
Mutation Taster		=299/1	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: rs137933845; hg19: chr16-88772963; COSMIC: COSV100371892; COSMIC: COSV100371892;