3-12510308-T-C

Variant names:

• chr3-12510308-T-C
• rs6766510
• NM_025265.4:c.909+5077T>C

Variant summary

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

The NM_025265.4(TSEN2):​c.909+5077T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 152,276 control chromosomes in the GnomAD database, including 791 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 0.092 (791 hom., cov: 32)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 22 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 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.909+5077T>C		intron	N/A	NP_079541.1
	TSEN2	NM_001321278.2		c.909+5077T>C		intron	N/A	NP_001308207.1
	TSEN2	NM_001145392.2		c.909+5077T>C		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.909+5077T>C		intron	N/A	ENSP00000284995.6
	TSEN2	ENST00000402228.7	TSL:1	c.909+5077T>C		intron	N/A	ENSP00000385976.3
	TSEN2	ENST00000454502.6	TSL:1	c.732+5077T>C		intron	N/A	ENSP00000392029.2

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13939 AN: 152158 Hom.: 788 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0364

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0737

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

GnomAD4 genome AF: 0.0917 AC: 13967 AN: 152276 Hom.: 791 Cov.: 32 AF XY: 0.0923 AC XY: 6870 AN XY: 74464

African (AFR) AF: 0.132 AC: 5469 AN: 41544

American (AMR) AF: 0.171 AC: 2615 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3470

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5182

South Asian (SAS) AF: 0.0362 AC: 175 AN: 4830

European-Finnish (FIN) AF: 0.0763 AC: 810 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0646 AC: 4395 AN: 68026

Other (OTH) AF: 0.0734 AC: 155 AN: 2112

Alfa AF: 0.0724 Hom.: 1646

Bravo AF: 0.104

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.77
PhyloP100		-1.4
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: rs6766510; hg19: chr3-12551807;