16-48261459-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_031490.5(LONP2):c.759T>G(p.His253Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,608,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

LONP2
NM_031490.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.398

Variant links:

Genes affected

LONP2 (HGNC:20598): (lon peptidase 2, peroxisomal) In human, peroxisomes function primarily to catalyze fatty acid beta-oxidation and, as a by-product, produce hydrogen peroxide and superoxide. The protein encoded by this gene is an ATP-dependent protease that likely plays a role in maintaining overall peroxisome homeostasis as well as proteolytically degrading peroxisomal proteins damaged by oxidation. The protein has an N-terminal Lon N substrate recognition domain, an ATPase domain, a proteolytic domain, and, in some isoforms, a C-terminal peroxisome targeting sequence. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

LONP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.062207162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LONP2	NM_031490.5 linkuse as main transcript	c.759T>G	p.His253Gln	missense_variant	5/15	ENST00000285737.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP2	ENST00000285737.9 linkuse as main transcript	c.759T>G	p.His253Gln	missense_variant	5/15	1	NM_031490.5	P1	Q86WA8-1
LONP2	ENST00000535754.5 linkuse as main transcript	c.627T>G	p.His209Gln	missense_variant	4/14	1			Q86WA8-2
LONP2	ENST00000416006.7 linkuse as main transcript	c.627T>G	p.His209Gln	missense_variant, NMD_transcript_variant	4/13	2
LONP2	ENST00000566755.5 linkuse as main transcript	c.759T>G	p.His253Gln	missense_variant, NMD_transcript_variant	5/14	5

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

248332

Hom.:

AF XY:

0.0000447

AC XY:

AN XY:

134360

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000298

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457024

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724960

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000812

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151376

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73898

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.759T>G (p.H253Q) alteration is located in exon 5 (coding exon 5) of the LONP2 gene. This alteration results from a T to G substitution at nucleotide position 759, causing the histidine (H) at amino acid position 253 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Benign

0.62

DEOGEN2

Benign

0.012

T;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.58

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

0.51

D;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.50

N;N

REVEL

Benign

0.15

Sift

Benign

0.61

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0060

B;.

Vest4

0.20

MutPred

0.24

Gain of MoRF binding (P = 0.0808);.;

MVP

0.33

MPC

0.26

ClinPred

0.024

GERP RS

0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.15

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over