3-12541569-A-G

Variant names:

• chr3-12541569-A-G
• rs2454431
• NM_001195279.2:c.431+291T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001195279.2(MKRN2OS):​c.431+291T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,962 control chromosomes in the GnomAD database, including 12,521 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (12521 hom., cov: 31)
• Consequence: MKRN2OS NM_001195279.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 6 publications found

Genes affected

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

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195279.2. 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
	MKRN2OS	NM_001195279.2	MANE Select	c.431+291T>C		intron	N/A	NP_001182208.1	H3BPM6
	MKRN2OS	NM_001378011.1		c.362+291T>C		intron	N/A	NP_001364940.1
	MKRN2OS	NM_001378010.1		c.221+291T>C		intron	N/A	NP_001364939.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKRN2OS	ENST00000564146.4	TSL:5 MANE Select	c.431+291T>C		intron	N/A	ENSP00000455385.3	H3BPM6
	MKRN2OS	ENST00000896064.1		c.362+291T>C		intron	N/A	ENSP00000566123.1
	MKRN2OS	ENST00000561645.2	TSL:5	n.*150+291T>C		intron	N/A	ENSP00000456723.1	H3BSJ0

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58661 AN: 151844 Hom.: 12499 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.367

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.386 AC: 58711 AN: 151962 Hom.: 12521 Cov.: 31 AF XY: 0.381 AC XY: 28321 AN XY: 74272

African (AFR) AF: 0.565 AC: 23376 AN: 41392

American (AMR) AF: 0.307 AC: 4679 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1087 AN: 3464

East Asian (EAS) AF: 0.0829 AC: 430 AN: 5186

South Asian (SAS) AF: 0.145 AC: 700 AN: 4814

European-Finnish (FIN) AF: 0.374 AC: 3943 AN: 10548

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23323 AN: 67978

Other (OTH) AF: 0.364 AC: 768 AN: 2112

Alfa AF: 0.374 Hom.: 1438

Bravo AF: 0.393

Asia WGS AF: 0.152 AC: 533 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.88
DANN	Benign	0.23
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs2454431; hg19: chr3-12583068;