Genetic Variant RTN2:p.Ile502Met (chr19-45486105-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005619.5(RTN2):c.1506C>G(p.Ile502Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I502I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RTN2
NM_005619.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.559

Publications

0 publications found

Variant links:

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]

RTN2 Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 12
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics

RTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTN2	NM_005619.5	MANE Select	c.1506C>G	p.Ile502Met	missense	Exon 10 of 11	NP_005610.1	O75298-1
RTN2	NM_206900.3		c.1287C>G	p.Ile429Met	missense	Exon 9 of 10	NP_996783.1	O75298-2
RTN2	NM_206901.3		c.486C>G	p.Ile162Met	missense	Exon 6 of 7	NP_996784.1	O75298-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTN2	ENST00000245923.9	TSL:1 MANE Select	c.1506C>G	p.Ile502Met	missense	Exon 10 of 11	ENSP00000245923.3	O75298-1
RTN2	ENST00000344680.8	TSL:1	c.1287C>G	p.Ile429Met	missense	Exon 9 of 10	ENSP00000345127.3	O75298-2
RTN2	ENST00000430715.6	TSL:1	c.486C>G	p.Ile162Met	missense	Exon 6 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111916

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.81

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

PhyloP100

-0.56

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.30

Sift

Benign

0.048

Sift4G

Uncertain

0.040

Polyphen

0.76

Vest4

0.71

MutPred

0.84

Gain of disorder (P = 0.1127)

MVP

0.51

MPC

0.66

ClinPred

0.93

GERP RS

-7.9

Varity_R

0.37

gMVP

0.67

Mutation Taster

=77/23

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over