3-12516464-G-C

Variant names:

• chr3-12516464-G-C
• rs761654828
• NM_025265.4:c.910-147G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 0 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.910-147G>C		intron	N/A	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.910-147G>C		intron	N/A	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.910-147G>C		intron	N/A	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.910-147G>C		intron	N/A	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.910-147G>C		intron	N/A	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.733-147G>C		intron	N/A	ENSP00000392029.2	Q8NCE0-4

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

African (AFR) AF: 0.000196 AC: 3 AN: 15298

American (AMR) AF: 0.000182 AC: 6 AN: 32944

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 91 AN: 18412

East Asian (EAS) AF: 0.00 AC: 0 AN: 31102

South Asian (SAS) AF: 0.000135 AC: 8 AN: 59472

European-Finnish (FIN) AF: 0.0151 AC: 553 AN: 36600

Middle Eastern (MID) AF: 0.000795 AC: 2 AN: 2516

European-Non Finnish (NFE) AF: 0.00492 AC: 1519 AN: 308960

Other (OTH) AF: 0.00301 AC: 88 AN: 29244

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

African (AFR) AF: 0.000193 AC: 8 AN: 41364

American (AMR) AF: 0.000197 AC: 3 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.00578 AC: 20 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0173 AC: 183 AN: 10558

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

European-Non Finnish (NFE) AF: 0.00509 AC: 345 AN: 67842

Other (OTH) AF: 0.00381 AC: 8 AN: 2102

Alfa AF: 0.00808 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.057
DANN	Benign	0.14
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs761654828; hg19: chr3-12557963;