19-45488915-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005619.5(RTN2):c.1313G>A(p.Arg438His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.404

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0771316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.1313G>A	p.Arg438His	missense_variant	7/11	ENST00000245923.9
RTN2	NM_206900.3	c.1094G>A	p.Arg365His	missense_variant	6/10
RTN2	NM_206901.3	c.293G>A	p.Arg98His	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.1313G>A	p.Arg438His	missense_variant	7/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457674 Hom.: 0 Cov.: 33 AF XY: 0.00000966 AC XY: 7 AN XY: 724684

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: 0.00000991

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 438 of the RTN2 protein (p.Arg438His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RTN2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.99
Dann	Uncertain	0.99
DEOGEN2	Benign	0.095	T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.67	T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.077	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.3	N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	4.9	N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.99	T;T;.;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.010	B;.;.;B
Vest4		0.030
MutPred		0.68		Gain of glycosylation at T436 (P = 0.0585);.;.;.;
MVP		0.068
MPC		0.34
ClinPred		0.28	T
GERP RS		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.39

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

Other links and lift over

dbSNP: rs1968089378; hg19: chr19-45992173;