rs41293385

Positions:

• chr3-12496514-C-G

Variant summary

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

The NM_025265.4(TSEN2):​c.272-4C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,613,898 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (35 hom.)
• Consequence: TSEN2 NM_025265.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005564
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.428

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]

TSEN2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-12496514-C-G is Benign according to our data. Variant chr3-12496514-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 160110.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 = 0.00348 (530/152304) while in subpopulation NFE AF= 0.00617 (420/68032). AF 95% confidence interval is 0.00569. There are 2 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN2	NM_025265.4	c.272-4C>G		splice_region_variant, intron_variant		ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11	c.272-4C>G		splice_region_variant, intron_variant		1	NM_025265.4	ENSP00000284995.6

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152186 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00679

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00617

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00409 AC: 1027 AN: 251312 Hom.: 2 AF XY: 0.00405 AC XY: 550 AN XY: 135846

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00852

Gnomad NFE exome AF: 0.00706

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00543 AC: 7937 AN: 1461594 Hom.: 35 Cov.: 31 AF XY: 0.00537 AC XY: 3902 AN XY: 727122

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00829

Gnomad4 NFE exome AF: 0.00650

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00348 AC: 530 AN: 152304 Hom.: 2 Cov.: 33 AF XY: 0.00350 AC XY: 261 AN XY: 74470

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00679

Gnomad4 NFE AF: 0.00617

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00527 Hom.: 1

Bravo AF: 0.00277

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00456

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	TSEN2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 22, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 06, 2013

- -

Pontoneocerebellar hypoplasia Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.6
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000056
dbscSNV1_RF	Benign	0.0
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: rs41293385; hg19: chr3-12538013;