3-12516464-G-C

Position:

• chr3-12516464-G-C

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.910-147G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 686,254 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0042 (22 hom.)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.35

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 3-12516464-G-C is Benign according to our data. Variant chr3-12516464-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1205801.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 = 0.00374 (567/151706) while in subpopulation NFE AF= 0.00509 (345/67842). AF 95% confidence interval is 0.00464. There are 6 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN2	NM_025265.4	c.910-147G>C		intron_variant		ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11	c.910-147G>C		intron_variant		1	NM_025265.4	ENSP00000284995.6

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 568 AN: 151588 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00578

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00508

Gnomad OTH AF: 0.00385

GnomAD4 exome AF: 0.00425 AC: 2270 AN: 534548 Hom.: 22 AF XY: 0.00421 AC XY: 1212 AN XY: 288178

Gnomad4 AFR exome AF: 0.000196

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000135

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00301

GnomAD4 genome AF: 0.00374 AC: 567 AN: 151706 Hom.: 6 Cov.: 30 AF XY: 0.00422 AC XY: 313 AN XY: 74176

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00578

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00381

Alfa AF: 0.00808 Hom.: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.057
DANN	Benign	0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs761654828; hg19: chr3-12557963;