rs145142315

Positions:

• chr3-12519111-C-G
• chr3-12519111-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025265.4(TSEN2):​c.1013C>G​(p.Thr338Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000481 in 1,614,190 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (2 hom.)
• Consequence: TSEN2 NM_025265.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.54

Genes affected

TSEN2 (HGNC:28422): (tRNA splicing endonuclease subunit 2) This gene encodes one of the subunits of the tRNA splicing endonuclease. This endonuclease catalyzes the first step in RNA splicing which is the removal of introns. Mutations in this gene have been associated with pontocerebellar hypoplasia type 2. A pseudogene has been identified on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

MKRN2OS (HGNC:40375): (MKRN2 opposite strand)

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014025748).
• BP6: Variant 3-12519111-C-G is Benign according to our data. Variant chr3-12519111-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 160101.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000482 (705/1461866) while in subpopulation MID AF= 0.00295 (17/5768). AF 95% confidence interval is 0.00188. There are 2 homozygotes in gnomad4_exome. There are 386 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN2	NM_025265.4	c.1013C>G	p.Thr338Arg	missense_variant	8/12	ENST00000284995.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN2	ENST00000284995.11	c.1013C>G	p.Thr338Arg	missense_variant	8/12	1	NM_025265.4	P2

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000736 AC: 185 AN: 251486 Hom.: 1 AF XY: 0.000780 AC XY: 106 AN XY: 135916

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000482 AC: 705 AN: 1461866 Hom.: 2 Cov.: 32 AF XY: 0.000531 AC XY: 386 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000404

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74502

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000502

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TSEN2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2019	- -

Pontocerebellar hypoplasia type 2B Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 25, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Pontoneocerebellar hypoplasia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.;T;.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.83	T;T;.;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.014	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.96	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Benign	0.080
Sift	Uncertain	0.0040	D;D;T;D;T;D
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.029, 0.11	.;.;B;.;B;B
Vest4		0.38, 0.32, 0.37, 0.35
MVP		0.43
MPC		0.037
ClinPred		0.045	T
GERP RS		5.4
Varity_R		0.22
gMVP		0.49

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: rs145142315; hg19: chr3-12560610;