rs146004780

Positions:

• chr19-45494800-T-C

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.285A>G​(p.Glu95=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,604,526 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (4 hom.)
• Consequence: RTN2 NM_005619.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0400

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=-0.83).
• BP6: Variant 19-45494800-T-C is Benign according to our data. Variant chr19-45494800-T-C is described in ClinVar as [Benign]. Clinvar id is 448175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45494800-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00349 (531/152286) while in subpopulation AFR AF= 0.0124 (514/41570). AF 95% confidence interval is 0.0115. There are 6 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 531 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.285A>G	p.Glu95=	synonymous_variant	3/11	ENST00000245923.9
RTN2	NM_206900.3	c.285A>G	p.Glu95=	synonymous_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.285A>G	p.Glu95=	synonymous_variant	3/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 530 AN: 152168 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000294

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000792 AC: 191 AN: 241226 Hom.: 0 AF XY: 0.000501 AC XY: 66 AN XY: 131634

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000366 AC: 531 AN: 1452240 Hom.: 4 Cov.: 32 AF XY: 0.000315 AC XY: 228 AN XY: 722824

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152286 Hom.: 6 Cov.: 32 AF XY: 0.00321 AC XY: 239 AN XY: 74458

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.00390

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 21, 2021

- -

RTN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.4
DANN	Benign	0.65

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: rs146004780; hg19: chr19-45998058;