19-45489371-G-A

Variant names:

• chr19-45489371-G-A
• rs977755323
• NM_005619.5:c.1216C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005619.5(RTN2):​c.1216C>T​(p.Arg406Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000773 in 1,423,944 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R406Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.01
• Publications: 0 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24131373).

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.1216C>T	p.Arg406Trp	missense	Exon 6 of 11	NP_005610.1	O75298-1
	RTN2	NM_206900.3		c.997C>T	p.Arg333Trp	missense	Exon 5 of 10	NP_996783.1	O75298-2
	RTN2	NM_206901.3		c.196C>T	p.Arg66Trp	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.1216C>T	p.Arg406Trp	missense	Exon 6 of 11	ENSP00000245923.3	O75298-1
	RTN2	ENST00000344680.8	TSL:1	c.997C>T	p.Arg333Trp	missense	Exon 5 of 10	ENSP00000345127.3	O75298-2
	RTN2	ENST00000430715.6	TSL:1	c.196C>T	p.Arg66Trp	missense	Exon 2 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00 AC: 0 AN: 191702 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000773 AC: 11 AN: 1423944 Hom.: 0 Cov.: 32 AF XY: 0.00000710 AC XY: 5 AN XY: 704702

African (AFR) AF: 0.0000916 AC: 3 AN: 32744

American (AMR) AF: 0.00 AC: 0 AN: 38242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.00 AC: 0 AN: 37668

South Asian (SAS) AF: 0.0000617 AC: 5 AN: 81024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093414

Other (OTH) AF: 0.00 AC: 0 AN: 59002

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.037
Eigen_PC	Benign	0.0067
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.52	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.18
Sift	Benign	0.033	D
Sift4G	Uncertain	0.049	D
Polyphen		0.73	P
Vest4		0.28
MutPred		0.68		Loss of methylation at R406 (P = 0.0096)
MVP		0.082
MPC		0.42
ClinPred		0.98	D
GERP RS		3.2
Varity_R		0.27
gMVP		0.54
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs977755323; hg19: chr19-45992629;