rs768449676

Positions:

chr19-45493253-TA-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_005619.5(RTN2):c.939delT(p.Thr314fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,612,998 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

RTN2
NM_005619.5 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: -0.146

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:

RTN2 (HGNC:):

RTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 19-45493253-TA-T is Pathogenic according to our data. Variant chr19-45493253-TA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378054.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr19-45493253-TA-T is described in Lovd as [Likely_pathogenic]. Variant chr19-45493253-TA-T is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN2	NM_005619.5 linkuse as main transcript	c.939delT	p.Thr314fs	frameshift_variant	5/11	ENST00000245923.9	NP_005610.1	O75298-1A8K7F2Q6GMT0
RTN2	NM_206900.3 linkuse as main transcript	c.814+912delT		intron_variant			NP_996783.1	O75298-2A8K7F2Q6GMT0
RTN2	NM_206901.3 linkuse as main transcript	c.-82delT		upstream_gene_variant			NP_996784.1	O75298-3A8K7F2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9 linkuse as main transcript	c.939delT	p.Thr314fs	frameshift_variant	5/11	1	NM_005619.5	ENSP00000245923.3		O75298-1

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000562

AC:

AN:

249254

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461066

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000883

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000416

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Reported in individuals with spastic paraplegia in published literature (PMID: 24123792, 32814230, 27165006); This variant is associated with the following publications: (PMID: 24123792, 25621899, 31589614, 28406212, 35684947, 32814230, 27165006, 34697415) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	RTN2: PS1:Moderate, PS4:Moderate, BS1 -

Spastic paraplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2023

This sequence change creates a premature translational stop signal (p.Thr314Leufs*8) in the RTN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RTN2 are known to be pathogenic (PMID: 22232211, 27165006). This variant is present in population databases (rs768449676, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 378054). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 24123792). -

Hereditary spastic paraplegia 12

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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