rs200512597

Variant names:

• chr19-45489377-C-T
• rs200512597
• NM_005619.5:c.1210G>A
• RTN2 p.Val404Met

Your query was ambiguous. Multiple possible variants found:

• chr19-45489377-C-T
• chr19-45489377-C-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_005619.5(RTN2):​c.1210G>A​(p.Val404Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,581,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.166
• Publications: 2 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11800861).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000986 (15/152154) while in subpopulation AMR AF = 0.000262 (4/15252). AF 95% confidence interval is 0.0000889. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005619.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	NM_005619.5	MANE Select	c.1210G>A	p.Val404Met	missense	Exon 6 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.991G>A	p.Val331Met	missense	Exon 5 of 10	NP_996783.1	O75298-2
	RTN2	NM_206901.3		c.190G>A	p.Val64Met	missense	Exon 2 of 7	NP_996784.1	O75298-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	ENST00000245923.9	TSL:1 MANE Select	c.1210G>A	p.Val404Met	missense	Exon 6 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.991G>A	p.Val331Met	missense	Exon 5 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000430715.6	TSL:1	c.190G>A	p.Val64Met	missense	Exon 2 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 152036 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000263

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000452 AC: 9 AN: 199128 AF XY: 0.0000659

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000707

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000575

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.0000616 AC: 88 AN: 1428976 Hom.: 0 Cov.: 32 AF XY: 0.0000551 AC XY: 39 AN XY: 707580

African (AFR) AF: 0.0000608 AC: 2 AN: 32882

American (AMR) AF: 0.0000513 AC: 2 AN: 39002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 37978

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.0000639 AC: 70 AN: 1096156

Other (OTH) AF: 0.000220 AC: 13 AN: 59216

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152154 Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 9 AN XY: 74386

African (AFR) AF: 0.0000482 AC: 2 AN: 41506

American (AMR) AF: 0.000262 AC: 4 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000838 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.054
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.17
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Varity_R		0.40
gMVP		0.41
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs200512597;

hg19: chr19-45992635;