Genetic Variant RTN2:c.1497+93C>A (chr19-45488378-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005619.5(RTN2):c.1497+93C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,211,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000033 ( 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

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	Effect	Exon Rank	Protein
RTN2	NM_005619.5	MANE Select	c.1497+93C>A	intron	N/A	NP_005610.1
RTN2	NM_206900.3		c.1278+93C>A	intron	N/A	NP_996783.1
RTN2	NM_206901.3		c.477+93C>A	intron	N/A	NP_996784.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RTN2	ENST00000245923.9	TSL:1 MANE Select	c.1497+93C>A	intron	N/A	ENSP00000245923.3
RTN2	ENST00000344680.8	TSL:1	c.1278+93C>A	intron	N/A	ENSP00000345127.3
RTN2	ENST00000430715.6	TSL:1	c.477+93C>A	intron	N/A	ENSP00000398178.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000330

AC:

AN:

1211288

Hom.:

AF XY:

0.00000331

AC XY:

AN XY:

605000

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27912

American (AMR)

AF:

0.00

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:

71832

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4424

European-Non Finnish (NFE)

AF:

0.00000110

AC:

AN:

908908

Other (OTH)

AF:

0.0000389

AC:

AN:

51478

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00448627), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.338

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

Cov.:

Alfa

AF:

0.00

Hom.:

204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

1.6

(source)

DANN

Benign

0.88

PhyloP100

-0.071

PromoterAI

0.029

Neutral

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over