16-48270018-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031490.5(LONP2):c.985C>T(p.Arg329Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,611,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: LONP2 NM_031490.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99

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]

ACMG classification

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=0.02783528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LONP2	NM_031490.5	c.985C>T	p.Arg329Cys	missense_variant, splice_region_variant	7/15	ENST00000285737.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP2	ENST00000285737.9	c.985C>T	p.Arg329Cys	missense_variant, splice_region_variant	7/15	1	NM_031490.5	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000197 AC: 49 AN: 249318 Hom.: 0 AF XY: 0.000193 AC XY: 26 AN XY: 134870

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00373

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000123 AC: 180 AN: 1459770 Hom.: 0 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 726096

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00358

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000481

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152050 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74242

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000546

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

The c.985C>T (p.R329C) alteration is located in exon 7 (coding exon 7) of the LONP2 gene. This alteration results from a C to T substitution at nucleotide position 985, causing the arginine (R) at amino acid position 329 to be replaced by a cysteine (C). 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	0.087
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.033
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.10
Sift	Benign	0.12	T;T
Sift4G	Benign	0.088	T;T
Polyphen		0.0020	B;.
Vest4		0.25
MVP		0.71
MPC		0.35
ClinPred		0.075	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.36

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

Other links and lift over

dbSNP: rs377497324; hg19: chr16-48303929;