19-45489419-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005619.5(RTN2):c.1168G>A(p.Gly390Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,606,818 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0028 ( 14 hom. )

Consequence

RTN2
NM_005619.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.241

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]

RTN2 links:

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]

PPM1N links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008215159).

BP6

Variant 19-45489419-C-T is Benign according to our data. Variant chr19-45489419-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 329549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45489419-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00236 (359/152080) while in subpopulation SAS AF= 0.00707 (34/4810). AF 95% confidence interval is 0.0052. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RTN2	NM_005619.5 linkuse as main transcript	c.1168G>A	p.Gly390Ser	missense_variant	6/11	ENST00000245923.9
RTN2	NM_206900.3 linkuse as main transcript	c.949G>A	p.Gly317Ser	missense_variant	5/10
RTN2	NM_206901.3 linkuse as main transcript	c.148G>A	p.Gly50Ser	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9 linkuse as main transcript	c.1168G>A	p.Gly390Ser	missense_variant	6/11	1	NM_005619.5		O75298-1

Frequencies

GnomAD3 genomes

AF:

0.00236

AC:

359

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00498

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00706

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00306

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00280

AC:

665

AN:

237610

Hom.:

AF XY:

0.00310

AC XY:

397

AN XY:

128170

show subpopulations

Gnomad AFR exome

AF:

0.000462

Gnomad AMR exome

AF:

0.00451

Gnomad ASJ exome

AF:

0.000613

Gnomad EAS exome

AF:

0.000114

Gnomad SAS exome

AF:

0.00656

Gnomad FIN exome

AF:

0.000650

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.00240

GnomAD4 exome

AF:

0.00279

AC:

4064

AN:

1454738

Hom.:

Cov.:

AF XY:

0.00304

AC XY:

2196

AN XY:

722964

show subpopulations

Gnomad4 AFR exome

AF:

0.000360

Gnomad4 AMR exome

AF:

0.00445

Gnomad4 ASJ exome

AF:

0.000655

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.00715

Gnomad4 FIN exome

AF:

0.000662

Gnomad4 NFE exome

AF:

0.00274

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152080

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000579

Gnomad4 AMR

AF:

0.00498

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00707

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00306

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00237

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00278

AC:

337

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	RTN2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 23, 2021

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2018

- -

Spastic paraplegia, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.0082

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.63

N;N;.;N

REVEL

Benign

0.040

Sift

Benign

0.39

T;T;.;T

Sift4G

Benign

0.44

T;T;T;T

Polyphen

0.97

D;.;.;B

Vest4

0.40

MVP

0.13

MPC

0.36

ClinPred

0.0063

GERP RS

2.3

Varity_R

0.061

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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