19-45489419-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G390G) has been classified as Uncertain significance.

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:9

Conservation

PhyloP100: 0.241

Publications

8 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 329549.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RTN2	NM_005619.5 link	c.1168G>A	p.Gly390Ser	missense_variant	Exon 6 of 11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3 link	c.949G>A	p.Gly317Ser	missense_variant	Exon 5 of 10		NP_996783.1
RTN2	NM_206901.3 link	c.148G>A	p.Gly50Ser	missense_variant	Exon 2 of 7		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9 link	c.1168G>A	p.Gly390Ser	missense_variant	Exon 6 of 11	1	NM_005619.5	ENSP00000245923.3

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

GnomAD2 exomes

AF:

0.00280

AC:

665

AN:

237610

AF XY:

0.00310

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 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

African (AFR)

AF:

0.000360

AC:

AN:

33374

American (AMR)

AF:

0.00445

AC:

194

AN:

43626

Ashkenazi Jewish (ASJ)

AF:

0.000655

AC:

AN:

25968

East Asian (EAS)

AF:

0.000102

AC:

AN:

39380

South Asian (SAS)

AF:

0.00715

AC:

605

AN:

84660

European-Finnish (FIN)

AF:

0.000662

AC:

AN:

52864

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00274

AC:

3041

AN:

1108984

Other (OTH)

AF:

0.00220

AC:

132

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

247

494

740

987

1234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152080

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

41448

American (AMR)

AF:

0.00498

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00707

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00306

AC:

208

AN:

67998

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00248

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTN2: BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 23, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

May 01, 2018

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia, autosomal dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.

PhyloP100

0.24

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

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over