rs758002007

Variant names:

• chr19-45494828-G-A
• rs758002007
• NM_005619.5:c.257C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-45494828-G-A
• chr19-45494828-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005619.5(RTN2):​c.257C>T​(p.Pro86Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,451,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.27

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12958327).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5	c.257C>T	p.Pro86Leu	missense_variant	Exon 3 of 11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.257C>T	p.Pro86Leu	missense_variant	Exon 3 of 10		NP_996783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.257C>T	p.Pro86Leu	missense_variant	Exon 3 of 11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000418 AC: 1 AN: 238992 Hom.: 0 AF XY: 0.00000765 AC XY: 1 AN XY: 130760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1451198 Hom.: 0 Cov.: 32 AF XY: 0.00000969 AC XY: 7 AN XY: 722314

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Jul 15, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with leucine at codon 86 of the RTN2 protein (p.Pro86Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases at a very low frequency (rs758002007, ExAC <0.01%) but has not been reported in the literature in individuals with a RTN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.27	B;P
Vest4		0.26
MutPred		0.36		Loss of glycosylation at P86 (P = 0.0244);Loss of glycosylation at P86 (P = 0.0244);
MVP		0.13
MPC		0.79
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.092
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758002007; hg19: chr19-45998086;