rs139232850

chr19-45494641-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005619.5(RTN2):c.444C>G(p.Gly148=) variant causes a synonymous change. The variant allele was found at a frequency of 0.00641 in 1,613,916 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (44 hom.)
• Consequence: RTN2 NM_005619.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.64

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-45494641-G-C is Benign according to our data. Variant chr19-45494641-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 240194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45494641-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00555 (845/152326) while in subpopulation NFE AF= 0.00776 (528/68022). AF 95% confidence interval is 0.00721. There are 5 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 846 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.444C>G	p.Gly148=	synonymous_variant	3/11	ENST00000245923.9
RTN2	NM_206900.3	c.444C>G	p.Gly148=	synonymous_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.444C>G	p.Gly148=	synonymous_variant	3/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152208 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00355

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00776

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00530 AC: 1330 AN: 250854 Hom.: 7 AF XY: 0.00525 AC XY: 712 AN XY: 135740

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00650 AC: 9501 AN: 1461590 Hom.: 44 Cov.: 32 AF XY: 0.00638 AC XY: 4639 AN XY: 727090

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.00151

Gnomad4 NFE exome AF: 0.00714

Gnomad4 OTH exome AF: 0.00767

GnomAD4 genome AF: 0.00555 AC: 845 AN: 152326 Hom.: 5 Cov.: 32 AF XY: 0.00495 AC XY: 369 AN XY: 74500

Gnomad4 AFR AF: 0.00356

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00776

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00834 Hom.: 5

Bravo AF: 0.00571

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2016	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, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 26, 2021	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 29, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

RTN2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs139232850; hg19: chr19-45997899; COSMIC: COSV99839353; COSMIC: COSV99839353;