19-45488954-C-G

Position:

• chr19-45488954-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005619.5(RTN2):​c.1274G>C​(p.Arg425Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RTN2 NM_005619.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.276

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1126858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN2	NM_005619.5	c.1274G>C	p.Arg425Pro	missense_variant	7/11	ENST00000245923.9	NP_005610.1
RTN2	NM_206900.3	c.1055G>C	p.Arg352Pro	missense_variant	6/10		NP_996783.1
RTN2	NM_206901.3	c.254G>C	p.Arg85Pro	missense_variant	3/7		NP_996784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9	c.1274G>C	p.Arg425Pro	missense_variant	7/11	1	NM_005619.5	ENSP00000245923.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243548 Hom.: 0 AF XY: 0.00000759 AC XY: 1 AN XY: 131706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 6.85e-7 AC: 1 AN: 1459398 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725732

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.0	N;N;.;N
REVEL	Benign	0.079
Sift	Benign	0.049	D;T;.;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.93	P;.;.;P
Vest4		0.25
MutPred		0.50		Gain of loop (P = 0.0312);.;.;.;
MVP		0.082
MPC		0.44
ClinPred		0.43	T
GERP RS		1.0
Varity_R		0.59
gMVP		0.81

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: rs35461805; hg19: chr19-45992212;