NM_005619.5:c.1607C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_005619.5(RTN2):c.1607C>T(p.Ala536Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RTN2
NM_005619.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.76

Publications

1 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor, autosomal recessive 11, with spasticity
Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, PanelApp Australia

RTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036129802).

BP6

Variant 19-45485739-G-A is Benign according to our data. Variant chr19-45485739-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 893520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00023 (35/152304) while in subpopulation AFR AF = 0.000818 (34/41564). AF 95% confidence interval is 0.000601. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTN2	NM_005619.5	MANE Select	c.1607C>T	p.Ala536Val	missense	Exon 11 of 11	NP_005610.1	O75298-1
RTN2	NM_206900.3		c.1388C>T	p.Ala463Val	missense	Exon 10 of 10	NP_996783.1	O75298-2
RTN2	NM_206901.3		c.587C>T	p.Ala196Val	missense	Exon 7 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.1607C>T	p.Ala536Val	missense	Exon 11 of 11	ENSP00000245923.3	O75298-1
RTN2	ENST00000344680.8	TSL:1	c.1388C>T	p.Ala463Val	missense	Exon 10 of 10	ENSP00000345127.3	O75298-2
RTN2	ENST00000430715.6	TSL:1	c.587C>T	p.Ala196Val	missense	Exon 7 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000841

AC:

AN:

249620

AF XY:

0.0000518

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0000867

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:

0.0000404

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111978

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000230

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000393

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 12 (1)

not provided (1)

RTN2-related disorder (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Benign

-0.069

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.67

M_CAP

Benign

0.0095

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

3.8

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.25

REVEL

Benign

0.056

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0060

Polyphen

0.29

Vest4

0.19

MVP

0.043

MPC

0.27

ClinPred

0.19

GERP RS

4.6

Varity_R

0.19

gMVP

0.41

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over