rs768449676

Variant names:

• chr19-45493253-TA-T
• rs768449676
• NM_005619.5:c.939delT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 9P and 5B. PVS1 PP5 BS1_Supporting BS2

The NM_005619.5(RTN2):​c.939delT​(p.Thr314LeufsTer8) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: -0.146

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 Uncertain_significance. Variant got 4 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].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000592 (9/151932) while in subpopulation SAS AF= 0.000417 (2/4796). AF 95% confidence interval is 0.0000734. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5	c.939delT	p.Thr314LeufsTer8	frameshift_variant	Exon 5 of 11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.814+912delT		intron_variant	Intron 4 of 9		NP_996783.1
RTN2	NM_206901.3	c.-82delT		upstream_gene_variant			NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.939delT	p.Thr314LeufsTer8	frameshift_variant	Exon 5 of 11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151816 Hom.: 0 Cov.: 33

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: 14 AN: 249254 Hom.: 1 AF XY: 0.0000592 AC XY: 8 AN XY: 135188

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: 83 AN: 1461066 Hom.: 1 Cov.: 31 AF XY: 0.0000647 AC XY: 47 AN XY: 726848

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: 9 AN: 151932 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74276

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.: 0

Bravo AF: 0.0000416

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Apr 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RTN2: PS1:Moderate, PS4:Moderate, BS1 -

Spastic paraplegia Pathogenic:1

Jan 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 24123792). ClinVar contains an entry for this variant (Variation ID: 378054). For these reasons, this variant has been classified as Pathogenic. -

Hereditary spastic paraplegia 12 Pathogenic:1

Mar 02, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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: rs768449676; hg19: chr19-45996511;