19-45488913-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The ENST00000245923.9(RTN2):​c.1315G>A​(p.Val439Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000298 in 1,609,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

RTN2
ENST00000245923.9 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.790
Variant links:
Genes affected
RTN2 (HGNC:10468): (reticulon 2) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Reticulon proteins also play an important role in the replication of positive-strand RNA (ssRNA) viruses. Mutations at this locus have been associated with autosomal dominant spastic paraplegia-12. [provided by RefSeq, Aug 2020]
PPM1N (HGNC:26845): (protein phosphatase, Mg2+/Mn2+ dependent 1N (putative)) Predicted to enable metal ion binding activity and protein serine/threonine phosphatase activity. Predicted to be involved in negative regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of canonical Wnt signaling pathway. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17316598).
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000281 (41/1457404) while in subpopulation EAS AF= 0.000708 (28/39540). AF 95% confidence interval is 0.000503. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RTN2NM_005619.5 linkuse as main transcriptc.1315G>A p.Val439Met missense_variant 7/11 ENST00000245923.9 NP_005610.1
RTN2NM_206900.3 linkuse as main transcriptc.1096G>A p.Val366Met missense_variant 6/10 NP_996783.1
RTN2NM_206901.3 linkuse as main transcriptc.295G>A p.Val99Met missense_variant 3/7 NP_996784.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RTN2ENST00000245923.9 linkuse as main transcriptc.1315G>A p.Val439Met missense_variant 7/111 NM_005619.5 ENSP00000245923 O75298-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152208
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000167
AC:
4
AN:
240216
Hom.:
0
AF XY:
0.00000770
AC XY:
1
AN XY:
129870
show subpopulations
Gnomad AFR exome
AF:
0.000131
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000112
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1457404
Hom.:
0
Cov.:
33
AF XY:
0.0000262
AC XY:
19
AN XY:
724506
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000708
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152326
Hom.:
0
Cov.:
32
AF XY:
0.0000268
AC XY:
2
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000144
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000606
Hom.:
0
Bravo
AF:
0.0000529
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 13, 2024Variant summary: RTN2 c.1315G>A (p.Val439Met) results in a conservative amino acid change located in the Reticulon domain (IPR003388) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 348820 control chromosomes, predominantly at a frequency of 0.0012 in the Japanese subpopulation (gnomAD, jMorp (Tadaka_2024)). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, however is not suggestive of a variant associated with autosomal dominant disease. To our knowledge, no occurrence of c.1315G>A in individuals affected with Spastic Paragplegia 12 and no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 37930845). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;.;T;.
Eigen
Uncertain
0.21
Eigen_PC
Benign
0.17
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.79
T;T;T;T
M_CAP
Benign
0.049
D
MetaRNN
Benign
0.17
T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
1.8
L;.;.;.
MutationTaster
Benign
0.91
D;N;N;N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-2.1
N;N;.;N
REVEL
Benign
0.18
Sift
Uncertain
0.0010
D;D;.;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;.;.;D
Vest4
0.42
MVP
0.22
MPC
0.57
ClinPred
0.59
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.19
gMVP
0.65

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.

Other links and lift over

dbSNP: rs144089256; hg19: chr19-45992171; API