dbSNP rs1603: RTN2:c.1497+93C>T (chr19-45488378-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_005619.5(RTN2):c.1497+93C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,363,494 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

RTN2
NM_005619.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0710

Publications

13 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0021 (320/152200) while in subpopulation AFR AF = 0.0072 (299/41534). AF 95% confidence interval is 0.00653. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RTN2	NM_005619.5 link	c.1497+93C>T	intron_variant	Intron 9 of 10	ENST00000245923.9	NP_005610.1	O75298-1A8K7F2Q6GMT0
RTN2	NM_206900.3 link	c.1278+93C>T	intron_variant	Intron 8 of 9		NP_996783.1	O75298-2A8K7F2Q6GMT0
RTN2	NM_206901.3 link	c.477+93C>T	intron_variant	Intron 5 of 6		NP_996784.1	O75298-3A8K7F2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RTN2	ENST00000245923.9 link	c.1497+93C>T		intron_variant	Intron 9 of 10	1	NM_005619.5	ENSP00000245923.3		O75298-1

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

320

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00722

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000196

AC:

238

AN:

1211294

Hom.:

AF XY:

0.000159

AC XY:

AN XY:

605002

show subpopulations

African (AFR)

AF:

0.00645

AC:

180

AN:

27912

American (AMR)

AF:

0.000506

AC:

AN:

37574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20722

East Asian (EAS)

AF:

0.00

AC:

AN:

38284

South Asian (SAS)

AF:

0.00

AC:

AN:

71836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50154

Middle Eastern (MID)

AF:

0.000904

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

908910

Other (OTH)

AF:

0.000330

AC:

AN:

51478

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00210

AC:

320

AN:

152200

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00720

AC:

299

AN:

41534

American (AMR)

AF:

0.000981

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.00

Hom.:

204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

2.8

(source)

DANN

Benign

0.89

PhyloP100

-0.071

PromoterAI

0.017

Neutral

(source)

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over