rs113981920

Variant names:

• chr3-12531653-A-G
• rs113981920
• NM_025265.4:c.1332A>G

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.1332A>G​(p.Lys444Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000659 in 1,603,158 control chromosomes in the GnomAD database, including 7 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 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (7 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.90
• Publications: 3 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=-0.53).
• BP6: Variant 3-12531653-A-G is Benign according to our data. Variant chr3-12531653-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 160106.
• BP7: Synonymous conserved (PhyloP=2.9 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000676 (103/152364) while in subpopulation AMR AF = 0.000915 (14/15302). AF 95% confidence interval is 0.000553. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.1332A>G	p.Lys444Lys	synonymous	Exon 11 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.1332A>G	p.Lys444Lys	synonymous	Exon 11 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.1332A>G	p.Lys444Lys	synonymous	Exon 11 of 12	NP_001138864.1	Q8NCE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.1332A>G	p.Lys444Lys	synonymous	Exon 11 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.1332A>G	p.Lys444Lys	synonymous	Exon 11 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.1155A>G	p.Lys385Lys	synonymous	Exon 12 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000983 AC: 247 AN: 251230 AF XY: 0.000869

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000546

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000657 AC: 953 AN: 1450794 Hom.: 7 Cov.: 27 AF XY: 0.000657 AC XY: 475 AN XY: 722538

African (AFR) AF: 0.000480 AC: 16 AN: 33300

American (AMR) AF: 0.000805 AC: 36 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 313 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000744 AC: 64 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00748 AC: 43 AN: 5746

European-Non Finnish (NFE) AF: 0.000319 AC: 351 AN: 1101902

Other (OTH) AF: 0.00217 AC: 130 AN: 60018

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74512

African (AFR) AF: 0.000144 AC: 6 AN: 41596

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00115 Hom.: 0

Bravo AF: 0.000729

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	1	not specified (1)
-	1	-	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.87
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs113981920; hg19: chr3-12573152;