rs45532933

chr19-45489444-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005619.5(RTN2):c.1143G>A(p.Ala381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,611,386 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (6 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (36 hom.)
• Consequence: RTN2 NM_005619.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.352

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 19-45489444-C-T is Benign according to our data. Variant chr19-45489444-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 240192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45489444-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00545 (828/151980) while in subpopulation NFE AF= 0.00674 (458/67984). AF 95% confidence interval is 0.00623. There are 6 homozygotes in gnomad4. There are 447 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 828 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.1143G>A	p.Ala381=	synonymous_variant	6/11	ENST00000245923.9
RTN2	NM_206900.3	c.924G>A	p.Ala308=	synonymous_variant	5/10
RTN2	NM_206901.3	c.123G>A	p.Ala41=	synonymous_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.1143G>A	p.Ala381=	synonymous_variant	6/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 828 AN: 151862 Hom.: 6 Cov.: 30

Gnomad AFR AF: 0.000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00611

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00674

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00668 AC: 1640 AN: 245594 Hom.: 7 AF XY: 0.00689 AC XY: 915 AN XY: 132748

Gnomad AFR exome AF: 0.000633

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.000769

Gnomad FIN exome AF: 0.0234

Gnomad NFE exome AF: 0.00871

Gnomad OTH exome AF: 0.00917

GnomAD4 exome AF: 0.00563 AC: 8223 AN: 1459406 Hom.: 36 Cov.: 32 AF XY: 0.00544 AC XY: 3951 AN XY: 725714

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00308

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000549

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.00590

Gnomad4 OTH exome AF: 0.00514

GnomAD4 genome AF: 0.00545 AC: 828 AN: 151980 Hom.: 6 Cov.: 30 AF XY: 0.00602 AC XY: 447 AN XY: 74290

Gnomad4 AFR AF: 0.000773

Gnomad4 AMR AF: 0.00610

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.00674

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00561 Hom.: 0

Bravo AF: 0.00437

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Spastic paraplegia, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

RTN2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	8.9
Dann	Benign	0.84

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: rs45532933; hg19: chr19-45992702;