dbSNP rs201387324: RTN2:p.Ala544Thr (chr19-45485716-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005619.5(RTN2):c.1630G>A(p.Ala544Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00041 in 1,613,908 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A544A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00044 ( 2 hom. )

Consequence

RTN2
NM_005619.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.32

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05960411).

BP6

Variant 19-45485716-C-T is Benign according to our data. Variant chr19-45485716-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 653220.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000158 (24/152282) while in subpopulation SAS AF = 0.000622 (3/4820). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.1630G>A	p.Ala544Thr	missense	Exon 11 of 11	NP_005610.1	O75298-1
RTN2	NM_206900.3		c.1411G>A	p.Ala471Thr	missense	Exon 10 of 10	NP_996783.1	O75298-2
RTN2	NM_206901.3		c.610G>A	p.Ala204Thr	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.1630G>A	p.Ala544Thr	missense	Exon 11 of 11	ENSP00000245923.3	O75298-1
RTN2	ENST00000344680.8	TSL:1	c.1411G>A	p.Ala471Thr	missense	Exon 10 of 10	ENSP00000345127.3	O75298-2
RTN2	ENST00000430715.6	TSL:1	c.610G>A	p.Ala204Thr	missense	Exon 7 of 7	ENSP00000398178.1	O75298-3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000160

AC:

AN:

249938

AF XY:

0.000229

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000205

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000436

AC:

637

AN:

1461626

Hom.:

Cov.:

AF XY:

0.000450

AC XY:

327

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000429

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000516

AC:

574

AN:

1111876

Other (OTH)

AF:

0.000331

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000158

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41570

American (AMR)

AF:

0.000131

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68024

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000418

Hom.:

Bravo

AF:

0.000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary spastic paraplegia 12 (2)

Inborn genetic diseases (1)

not provided (1)

Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.81

M_CAP

Benign

0.022

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.69

PhyloP100

3.3

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.10

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.20

MVP

0.093

MPC

0.27

ClinPred

0.10

GERP RS

4.1

Varity_R

0.35

gMVP

0.37

Mutation Taster

=79/21

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