chr19-45494641-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005619.5(RTN2):c.444C>G(p.Gly148Gly) variant causes a synonymous change. The variant allele was found at a frequency of 0.00641 in 1,613,916 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 44 hom. )

Consequence

RTN2
NM_005619.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.64

Publications

4 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 links:

PPM1N (HGNC:26845): (protein phosphatase, Mg2+/Mn2+ dependent 1N (putative)) Predicted to enable metal ion binding activity and protein serine/threonine phosphatase activity. Predicted to be involved in negative regulation of I-kappaB kinase/NF-kappaB signaling and positive regulation of canonical Wnt signaling pathway. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PPM1N links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 19-45494641-G-C is Benign according to our data. Variant chr19-45494641-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00555 (845/152326) while in subpopulation NFE AF = 0.00776 (528/68022). AF 95% confidence interval is 0.00721. There are 5 homozygotes in GnomAd4. There are 369 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTN2	NM_005619.5	MANE Select	c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 11	NP_005610.1
	RTN2	NM_206900.3		c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 10	NP_996783.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RTN2	ENST00000245923.9	TSL:1 MANE Select	c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 11	ENSP00000245923.3
RTN2	ENST00000344680.8	TSL:1	c.444C>G	p.Gly148Gly	synonymous	Exon 3 of 10	ENSP00000345127.3
RTN2	ENST00000591286.5	TSL:1	n.444C>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000467863.1

Frequencies

GnomAD3 genomes

AF:

0.00556

AC:

846

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00355

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00776

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.00530

AC:

1330

AN:

250854

AF XY:

0.00525

show subpopulations

Gnomad AFR exome

AF:

0.00284

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.0167

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00122

Gnomad NFE exome

AF:

0.00764

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00650

AC:

9501

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00638

AC XY:

4639

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

33480

American (AMR)

AF:

0.00335

AC:

150

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

465

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00290

AC:

250

AN:

86258

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

53124

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00714

AC:

7938

AN:

1112010

Other (OTH)

AF:

0.00767

AC:

463

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

613

1225

1838

2450

3063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

296

592

888

1184

1480

<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:

0.00555

AC:

845

AN:

152326

Hom.:

Cov.:

AF XY:

0.00495

AC XY:

369

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00356

AC:

148

AN:

41574

American (AMR)

AF:

0.00457

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000659

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00776

AC:

528

AN:

68022

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

130

173

216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00834

Hom.:

Bravo

AF:

0.00571

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00992

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 31, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

May 26, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RTN2: BP4, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spastic paraplegia

Benign:1

Nov 29, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

3.6

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over