11-47448832-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_005055.5(RAPSN):c.133G>A(p.Val45Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V45L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.57

Publications

12 publications found

Variant links:

Genes affected

RAPSN (HGNC:9863): (receptor associated protein of the synapse) This gene encodes a member of a family of proteins that are receptor associated proteins of the synapse. The encoded protein contains a conserved cAMP-dependent protein kinase phosphorylation site, and plays a critical role in clustering and anchoring nicotinic acetylcholine receptors at synaptic sites by linking the receptors to the underlying postsynaptic cytoskeleton, possibly by direct association with actin or spectrin. Mutations in this gene may play a role in postsynaptic congenital myasthenic syndromes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Apr 2011]

RAPSN Gene-Disease associations (from GenCC):

fetal akinesia deformation sequence 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
neuromuscular disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
congenital myasthenic syndrome 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
fetal akinesia deformation sequence 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAPSN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-47448832-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2175150.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

PP5

Variant 11-47448832-C-T is Pathogenic according to our data. Variant chr11-47448832-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5 link	c.133G>A	p.Val45Met	missense_variant	Exon 1 of 8	ENST00000298854.7	NP_005046.2	Q13702-1A0A0S2Z4F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPSN	ENST00000298854.7 link	c.133G>A	p.Val45Met	missense_variant	Exon 1 of 8	1	NM_005055.5	ENSP00000298854.2	Q13702-1
RAPSN	ENST00000352508.7 link	c.133G>A	p.Val45Met	missense_variant	Exon 1 of 6	1		ENSP00000298853.3	Q13702-2
RAPSN	ENST00000529341.1 link	c.133G>A	p.Val45Met	missense_variant	Exon 1 of 5	1		ENSP00000431732.1	E9PK11
RAPSN	ENST00000524487.5 link	c.133G>A	p.Val45Met	missense_variant	Exon 1 of 7	5		ENSP00000435551.2	E9PJP9

Frequencies

GnomAD3 genomes

AF:

0.0000525

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251066

AF XY:

0.0000442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000155

AC:

227

AN:

1461574

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727126

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000194

AC:

216

AN:

1112000

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000431

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jan 02, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with the V45M variant markedly decreasing the ability of rapsyn to cocluster with AChR subunits (PMID: 17594401); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36815443, 35488281, 37334785, 17878953, 31981491, 28495245, 19620612, 28492532, 17594401, 34426522, 31771860, 33820833, 32906206, 38511267, 38278647) -

Sep 29, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2019

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. -

Fetal akinesia deformation sequence 2

Pathogenic:2

Jan 10, 2022

Istanbul Faculty of Medicine, Istanbul University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Lethal phenotype, identified in a sibship of two -

Mar 01, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 11

Pathogenic:2

Jul 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with foetal akinesia deformation sequence 2 (MIM#618388) and congenital myasthenic syndrome 11 associated with acetylcholine receptor deficiency (MIM#616326). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (11 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated N terminal myristoylation and linker region (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in eight individuals with RAPSN-related conditions, including one individual who was also compound heterozygous for p.(Asn88Lys) (ClinVar, PMIDs: 19620612, 17594401). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies have shown that this variant decreases the ability of RAPSN to cluster with acetylcholine receptors (PMID: 17594401). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2

Pathogenic:1

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 45 of the RAPSN protein (p.Val45Met). This variant is present in population databases (rs121909254, gnomAD 0.007%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 19620612). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8055). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAPSN protein function. Experimental studies have shown that this missense change affects RAPSN function (PMID: 17594401). For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.079

T;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

1.7

L;L;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.58

N;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.81

MutPred

0.77

Gain of MoRF binding (P = 0.0867);Gain of MoRF binding (P = 0.0867);Gain of MoRF binding (P = 0.0867);Gain of MoRF binding (P = 0.0867);

MVP

0.86

MPC

0.64

ClinPred

0.52

GERP RS

5.6

PromoterAI

0.038

Neutral

(source)

Varity_R

0.26

gMVP

0.46

Mutation Taster

=3/97

disease causing (ClinVar)

(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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11-47448832-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over