chr19-45488954-C-T

Position:

chr19-45488954-C-T

Variant summary

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

The ENST00000245923.9(RTN2):c.1274G>A(p.Arg425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,611,644 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

RTN2
ENST00000245923.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.276

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=0.0033495426).

BP6

Variant 19-45488954-C-T is Benign according to our data. Variant chr19-45488954-C-T is described in ClinVar as [Benign]. Clinvar id is 448171.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00166 (252/152246) while in subpopulation AFR AF= 0.00537 (223/41562). AF 95% confidence interval is 0.00479. There are 2 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RTN2	NM_005619.5 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	7/11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3 linkuse as main transcript	c.1055G>A	p.Arg352Gln	missense_variant	6/10		NP_996783.1
RTN2	NM_206901.3 linkuse as main transcript	c.254G>A	p.Arg85Gln	missense_variant	3/7		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9 linkuse as main transcript	c.1274G>A	p.Arg425Gln	missense_variant	7/11	1	NM_005619.5	ENSP00000245923		O75298-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00538

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.0000588

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000435

AC:

106

AN:

243548

Hom.:

AF XY:

0.000402

AC XY:

AN XY:

131706

show subpopulations

Gnomad AFR exome

AF:

0.00605

Gnomad AMR exome

AF:

0.000176

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:

0.0000364

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000209

AC:

305

AN:

1459398

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

725732

show subpopulations

Gnomad4 AFR exome

AF:

0.00682

Gnomad4 AMR exome

AF:

0.000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.00166

AC:

252

AN:

152246

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

123

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00537

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000279

Hom.:

Bravo

AF:

0.00192

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000503

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 31, 2016

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.061

T;.;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.0033

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.040

N;.;.;.

MutationTaster

Benign

0.99

N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

1.4

N;N;.;N

REVEL

Benign

0.040

Sift

Benign

0.27

T;T;.;T

Sift4G

Benign

0.86

T;T;T;T

Polyphen

0.17

B;.;.;B

Vest4

0.11

MVP

0.043

MPC

0.32

ClinPred

0.019

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.067

gMVP

0.32

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