rs17036879

chr3-12519061-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025265.4(TSEN2):c.963G>A(p.Glu321=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,614,074 control chromosomes in the GnomAD database, including 463 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (48 hom., cov: 32)
  • Exomes 𝑓: 0.017 (415 hom.)
• Consequence: TSEN2 NM_025265.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0220

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-12519061-G-A is Benign according to our data. Variant chr3-12519061-G-A is described in ClinVar as [Benign]. Clinvar id is 137751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN2	NM_025265.4	c.963G>A	p.Glu321=	splice_region_variant, synonymous_variant	8/12	ENST00000284995.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN2	ENST00000284995.11	c.963G>A	p.Glu321=	splice_region_variant, synonymous_variant	8/12	1	NM_025265.4	P2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2837 AN: 152138 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0326

GnomAD3 exomes AF: 0.0228 AC: 5744 AN: 251450 Hom.: 127 AF XY: 0.0236 AC XY: 3211 AN XY: 135896

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0339

Gnomad SAS exome AF: 0.0575

Gnomad FIN exome AF: 0.00966

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0168 AC: 24594 AN: 1461818 Hom.: 415 Cov.: 32 AF XY: 0.0176 AC XY: 12830 AN XY: 727212

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0368

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.0432

Gnomad4 SAS exome AF: 0.0552

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0187 AC: 2844 AN: 152256 Hom.: 48 Cov.: 32 AF XY: 0.0202 AC XY: 1506 AN XY: 74456

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0378

Gnomad4 SAS AF: 0.0595

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.0355

Alfa AF: 0.0128 Hom.: 2

Bravo AF: 0.0195

Asia WGS AF: 0.0920 AC: 319 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0157

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Pontoneocerebellar hypoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	6.7
Dann	Benign	0.88

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: rs17036879; hg19: chr3-12560560;