19-45488955-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005619.5(RTN2):c.1273C>T(p.Arg425Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,611,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.95

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023472726).
• BP6: Variant 19-45488955-G-A is Benign according to our data. Variant chr19-45488955-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2193792.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000164 (25/152306) while in subpopulation SAS AF= 0.00207 (10/4828). AF 95% confidence interval is 0.00112. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN2	NM_005619.5	c.1273C>T	p.Arg425Trp	missense_variant	7/11	ENST00000245923.9
RTN2	NM_206900.3	c.1054C>T	p.Arg352Trp	missense_variant	6/10
RTN2	NM_206901.3	c.253C>T	p.Arg85Trp	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN2	ENST00000245923.9	c.1273C>T	p.Arg425Trp	missense_variant	7/11	1	NM_005619.5

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000210 AC: 51 AN: 243202 Hom.: 0 AF XY: 0.000296 AC XY: 39 AN XY: 131542

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1459350 Hom.: 0 Cov.: 33 AF XY: 0.000163 AC XY: 118 AN XY: 725710

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000676

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74470

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.2	L;.;.;.
MutationTaster	Benign	0.57	D;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.38
MVP		0.068
MPC		0.85
ClinPred		0.10	T
GERP RS		4.5
Varity_R		0.60
gMVP		0.54

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: rs147161725; hg19: chr19-45992213;