rs117156117

Positions:

• chr19-45495123-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005619.5(RTN2):​c.51A>G​(p.Thr17Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,614,148 control chromosomes in the GnomAD database, including 405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (348 hom.)
• Consequence: RTN2 NM_005619.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.10

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]

RTN2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-45495123-T-C is Benign according to our data. Variant chr19-45495123-T-C is described in ClinVar as [Benign]. Clinvar id is 383326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN2	NM_005619.5	c.51A>G	p.Thr17Thr	synonymous_variant	2/11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.51A>G	p.Thr17Thr	synonymous_variant	2/10		NP_996783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.51A>G	p.Thr17Thr	synonymous_variant	2/11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes AF: 0.00943 AC: 1435 AN: 152180 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0525

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0196 AC: 4929 AN: 251412 Hom.: 257 AF XY: 0.0156 AC XY: 2117 AN XY: 135880

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0534

Gnomad SAS exome AF: 0.00385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00507 AC: 7405 AN: 1461850 Hom.: 348 Cov.: 33 AF XY: 0.00455 AC XY: 3311 AN XY: 727232

Gnomad4 AFR exome AF: 0.00116

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0442

Gnomad4 SAS exome AF: 0.00391

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00945 AC: 1439 AN: 152298 Hom.: 57 Cov.: 32 AF XY: 0.0106 AC XY: 792 AN XY: 74454

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.0679

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0522

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00213 Hom.: 5

Bravo AF: 0.0161

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: 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	Athena Diagnostics	Dec 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 12, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.61

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: rs117156117; hg19: chr19-45998381;