rs10510421

Variant names:

• chr3-12485743-C-T
• rs10510421
• NM_025265.4:c.-18+863C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025265.4(TSEN2):​c.-18+863C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0637 in 152,238 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.064 (672 hom., cov: 32)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025265.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.-18+863C>T		intron	N/A	NP_079541.1
	TSEN2	NM_001321278.2		c.-18+1226C>T		intron	N/A	NP_001308207.1
	TSEN2	NM_001145392.2		c.-18+1115C>T		intron	N/A	NP_001138864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.-18+863C>T		intron	N/A	ENSP00000284995.6
	TSEN2	ENST00000402228.7	TSL:1	c.-18+1115C>T		intron	N/A	ENSP00000385976.3
	TSEN2	ENST00000454502.6	TSL:1	c.-18+1226C>T		intron	N/A	ENSP00000392029.2

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 9679 AN: 152120 Hom.: 669 Cov.: 32

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0681

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0289

Gnomad SAS AF: 0.0608

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0718

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0637 AC: 9693 AN: 152238 Hom.: 672 Cov.: 32 AF XY: 0.0635 AC XY: 4725 AN XY: 74452

African (AFR) AF: 0.167 AC: 6915 AN: 41496

American (AMR) AF: 0.0681 AC: 1042 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0292 AC: 151 AN: 5180

South Asian (SAS) AF: 0.0600 AC: 290 AN: 4832

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1001 AN: 68022

Other (OTH) AF: 0.0743 AC: 157 AN: 2112

Alfa AF: 0.0468 Hom.: 62

Bravo AF: 0.0717

Asia WGS AF: 0.0990 AC: 343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.60
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs10510421; hg19: chr3-12527242;