Genetic Variant NM_198461.4:c.2089G>T (chr2-100284474-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_198461.4(LONRF2):c.2089G>T(p.Ala697Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000188 in 1,597,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LONRF2
NM_198461.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.67

Variant links:

Genes affected

LONRF2 (HGNC:24788): (LON peptidase N-terminal domain and ring finger 2) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

LONRF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3309877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LONRF2	NM_198461.4 link	c.2089G>T	p.Ala697Ser	missense_variant	Exon 12 of 12	ENST00000393437.8	NP_940863.3	Q1L5Z9-1
LONRF2	NM_001371783.1 link	c.1360G>T	p.Ala454Ser	missense_variant	Exon 13 of 13		NP_001358712.1
LONRF2	XM_047443537.1 link	c.1360G>T	p.Ala454Ser	missense_variant	Exon 12 of 12		XP_047299493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LONRF2	ENST00000393437.8 link	c.2089G>T	p.Ala697Ser	missense_variant	Exon 12 of 12	5	NM_198461.4	ENSP00000377086.3		Q1L5Z9-1
LONRF2	ENST00000409647.1 link	c.1360G>T	p.Ala454Ser	missense_variant	Exon 12 of 12	2		ENSP00000386823.1		Q1L5Z9-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.00000870

AC:

AN:

229952

Hom.:

AF XY:

0.00000800

AC XY:

AN XY:

125004

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000191

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717342

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:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

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

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2089G>T (p.A697S) alteration is located in exon 12 (coding exon 12) of the LONRF2 gene. This alteration results from a G to T substitution at nucleotide position 2089, causing the alanine (A) at amino acid position 697 to be replaced by a serine (S). 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

0.095

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.33

T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.5

D;N

REVEL

Uncertain

0.41

Sift

Benign

0.060

T;T

Sift4G

Uncertain

0.049

D;T

Polyphen

0.97

D;.

Vest4

0.15

MVP

0.64

MPC

0.75

ClinPred

0.91

GERP RS

5.0

Varity_R

0.31

gMVP

0.49

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