3-12532712-C-T

Variant names:

• chr3-12532712-C-T
• rs75288720
• NM_025265.4:c.1389C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_025265.4(TSEN2):​c.1389C>T​(p.Asp463Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,613,984 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.90
• 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]

MKRN2OS (HGNC:40375): (MKRN2 opposite strand)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 3-12532712-C-T is Benign according to our data. Variant chr3-12532712-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160108.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00284 (432/152208) while in subpopulation AFR AF = 0.00995 (413/41526). AF 95% confidence interval is 0.00915. There are 3 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1389C>T	p.Asp463Asp	synonymous	Exon 12 of 12	NP_079541.1
	TSEN2	NM_001145392.2		c.1389C>T	p.Asp463Asp	synonymous	Exon 12 of 12	NP_001138864.1
	TSEN2	NM_001321277.2		c.1389C>T	p.Asp463Asp	synonymous	Exon 12 of 12	NP_001308206.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.1389C>T	p.Asp463Asp	synonymous	Exon 12 of 12	ENSP00000284995.6
	TSEN2	ENST00000402228.7	TSL:1	c.1389C>T	p.Asp463Asp	synonymous	Exon 12 of 12	ENSP00000385976.3
	TSEN2	ENST00000454502.6	TSL:1	c.1212C>T	p.Asp404Asp	synonymous	Exon 13 of 13	ENSP00000392029.2

Frequencies

GnomAD3 genomes AF: 0.00285 AC: 434 AN: 152090 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000752 AC: 189 AN: 251440 AF XY: 0.000508

Gnomad AFR exome AF: 0.0106

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1461776 Hom.: 3 Cov.: 31 AF XY: 0.000297 AC XY: 216 AN XY: 727192

African (AFR) AF: 0.0117 AC: 393 AN: 33476

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111932

Other (OTH) AF: 0.000745 AC: 45 AN: 60390

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152208 Hom.: 3 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74438

African (AFR) AF: 0.00995 AC: 413 AN: 41526

American (AMR) AF: 0.000916 AC: 14 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00152 Hom.: 1

Bravo AF: 0.00321

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Pontocerebellar hypoplasia type 2B (1)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.15
DANN	Benign	0.86
PhyloP100		-2.9
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs75288720; hg19: chr3-12574211;