rs62637658

Variant names:

• chr3-12489866-A-C
• rs62637658
• NM_025265.4:c.66A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-12489866-A-C
• chr3-12489866-A-G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_025265.4(TSEN2):​c.66A>C​(p.Pro22Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000577 in 1,614,100 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.24
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 3-12489866-A-C is Benign according to our data. Variant chr3-12489866-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00298 (454/152298) while in subpopulation AFR AF = 0.0103 (429/41546). AF 95% confidence interval is 0.00952. 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.66A>C	p.Pro22Pro	synonymous	Exon 2 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.66A>C	p.Pro22Pro	synonymous	Exon 2 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.66A>C	p.Pro22Pro	synonymous	Exon 2 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.66A>C	p.Pro22Pro	synonymous	Exon 2 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.66A>C	p.Pro22Pro	synonymous	Exon 2 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.66A>C	p.Pro22Pro	synonymous	Exon 2 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 152180 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251378 AF XY: 0.000478

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000326 AC: 477 AN: 1461802 Hom.: 2 Cov.: 32 AF XY: 0.000294 AC XY: 214 AN XY: 727202

African (AFR) AF: 0.0125 AC: 418 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.000596 AC: 36 AN: 60392

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74476

African (AFR) AF: 0.0103 AC: 429 AN: 41546

American (AMR) AF: 0.00157 AC: 24 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00134 Hom.: 0

Bravo AF: 0.00357

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	TSEN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.2
DANN	Benign	0.64
PhyloP100		-2.2
PromoterAI		-0.0096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs62637658; hg19: chr3-12531365;