rs104894299

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM1PM2PP5_Very_StrongBP4

The NM_005055.5(RAPSN):c.264C>A(p.Asn88Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 1 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:33O:1

Conservation

PhyloP100: 5.31

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_005055.5

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47448079-G-T is Pathogenic according to our data. Variant chr11-47448079-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47448079-G-T is described in Lovd as [Pathogenic]. Variant chr11-47448079-G-T is described in Lovd as [Likely_pathogenic]. Variant chr11-47448079-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.112422615).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	2/8	ENST00000298854.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	2/8	1	NM_005055.5	P1	Q13702-1
RAPSN	ENST00000352508.7 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	2/6	1			Q13702-2
RAPSN	ENST00000529341.1 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	2/5	1
RAPSN	ENST00000524487.5 linkuse as main transcript	c.264C>A	p.Asn88Lys	missense_variant	2/7	5

Frequencies

GnomAD3 genomes

AF:

0.00148

AC:

225

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00156

AC:

391

AN:

250910

Hom.:

AF XY:

0.00141

AC XY:

192

AN XY:

135702

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000839

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000417

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00209

AC:

3048

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1463

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00184

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000638

Gnomad4 FIN exome

AF:

0.000450

Gnomad4 NFE exome

AF:

0.00247

Gnomad4 OTH exome

AF:

0.00199

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152228

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.00235

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00206

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:33Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2021	Published functional studies demonstrate a damaging effect, including diminished coclustering of AChR with rapsyn and impaired post-synaptic morphological development (Ohno et al., 2002; Cossins et al., 2006); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 15328566, 12730725, 19620612, 25194721, 15482960, 11791205, 29053879, 16945936, 21228398, 12929188, 24319099, 20157724, 15286164, 26927095, 15036330, 12796535, 12807980, 17190963, 14659409, 21305573, 29189923, 29054425, 30266223, 30028532, 31226102, 27397848, 32070632, 31980526, 32403337, 31127727, 32528171) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RAPSN: PM3:Very Strong, PM2:Supporting, PP1, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 21, 2019	The best available variant frequency is more than 10 times the disease allele frequency, and is at least 0.1%. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism. Very strong co-segregation with disease in affected individuals from a single family. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Congenital myasthenic syndrome 11

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Feb 02, 2021	The RAPSN c.264C>A variant is classified as a PATHOGENIC VARIANT (PS3, PS4, PP1, PP3, PP5) This variant is a single nucleotide change from a cytosine to an adenine at position 264 which is predicted to change the Asparagine at position 88 in the protein to Lysine. The variant is in exon 2 and is located in protein domain: tetratricopeptide repeat, of the RAPSN gene. This variant is a common pathogenic variant in the RAPSN gene causing congenital myasthenic syndrome (CMSs), and has been reported in many individuals with CMSs in both the homozygous or compound heterozygous state (PS4). Further, this variant has also been shown to segregate with disease in multiples families with CMSs (PP1) (PMID: 12796535, 16945936, 14504330). In vitro functional studies have demonstrated that this variant reduced the recruitment of the acetylcholine receptor (AChR) to rapsyn clusters, as well as impaired postsynaptic morphological development (PMID: 11791205, 16945936) (PS3). The variant is in dbSNP (rs104894299) and has been reported in population databases (gnomAD: 429/282254, 0 homozygote). The variant has been reported in ClinVar (Variation ID: 8046) and HGMD (Accession ID: CM020758) as pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Aug 20, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Oct 10, 2022	PS3, PM1, PM2, PP3, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 fetal 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 asparagine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 429 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It is a well-known pathogenic variant, and it has been reported in multiple individuals with congenital myasthenic syndrome (ClinVar, PMID: 29054425). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 17, 2017	The RAPSN c.264C>A (p.Asn88Lys) variant is a well-documented pathogenic missense variant for congenital myasthenic syndrome (CMS). To date, all patients with CMS who carry a variant in the RASPN gene carry the p.Asn88Lys variant on at least one allele (Richard et al. 2003). Across a selection of the available literature, the p.Asn88Lys variant is reported in 80 out of 216 patients, including in 31 homozygotes and 49 compound heterozygotes. The variant is also reported in three asymptomatic homozygous mothers of patients (Ohno et al. 2002; Burke et al. 2003; Muller et al. 2003; Richard et al. 2003; Maselli et al. 2003; Dunne et al. 2003; Muller et al. 2004; Skeie et al. 2006; Milone et al. 2009). The p.Asn88Lys variant was found in three of 720 total controls and is reported at a frequency of 0.00398 in the European population of the 1000 Genomes Project. Haplotype analysis suggests that the p.Asn88Lys variant may be derived from a single founder event in an ancient Indo-European population (Muller et al. 2004). The Asn88 residue is conserved (Ohno et al. 2002) and is located in a leucine zipper motif which is involved in acetylcholine receptor clustering (Dunne et al. 2003). Expression studies in HEK cells showed that the p.Asn88Lys variant significantly reduced the recruitment of the acetylcholine receptor to rapsyn clusters (Ohno et al. 2002). Based on the collective evidence, the p.Asn88Lys variant is classified as pathogenic for congenital myasthenic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 26, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PS1,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Mar 29, 2023	This variant was observed in heterozygosity with variant c.123del -

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

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 88 of the RAPSN protein (p.Asn88Lys). This variant is present in population databases (rs104894299, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12796535, 14504330, 16945936). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 12796535, 14504330, 16945936). ClinVar contains an entry for this variant (Variation ID: 8046). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAPSN protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16945936). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jan 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

Congenital myasthenic syndrome

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2022	Variant summary: RAPSN c.264C>A (p.Asn88Lys) results in a non-conservative amino acid change located in the Tetratricopeptide repeat (IPR019734) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 250910 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RAPSN causing Congenital Myasthenic Syndrome (0.0016 vs 0.0016). c.264C>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Myasthenic Syndrome and is considered a European founder mutation (e.g. Ohno_2002, Maselli_2003, Richard_2003, Cossins_2006, Abicht_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant affects the association of rapsyn with AChR and dramatically reduces the stability of AChR clusters (Ohno_2002, Cossins_2006). Sixteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital myasthenic syndrome 4C

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 17, 2014	The Asn88Lys variant in RAPSN has been previously identified in many individuals with congenital myasthenic syndrome and has been shown to segregate with disease in several affected family members (Ohno 2002, Dunne 2003, Richard 2003, Muller 2003, Banwell 2004, Yasaki 2004, Muller 2004, Ioos 2004, Cossins 2006, Skeie 2006, Milone 2009, Brugoni 2010, Bell 2011, Alseth 2011). This variant has been identified in 0.01% (13/8596) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs104894299). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Functional studies indicate the Asn88Lys variant results in reduced co-localization with the acetylcholine receptor (AChR) (Cossins 2006). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies and functional evidence. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.264C>A (p.N88K) alteration is located in exon 2 (coding exon 2) of the RAPSN gene. This alteration results from a C to A substitution at nucleotide position 264, causing the asparagine (N) at amino acid position 88 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.15% (429/282254) total alleles studied. The highest observed frequency was 0.26% (332/128732) of European (non-Finnish) alleles. This alteration is the most common mutation causing congenital myasthenic syndrome in Europeans. It has been reported in many affected homozygotes and heterozygotes with a second RAPSN alteration (Ohno, 2002; Abicht, 2003; Dunne, 2003; Maselli, 2003; Müller, 2003; Richard, 2003; Müller, 2004; Cossins, 2006; Milone, 2009). This amino acid position is highly conserved in available vertebrate species. Functional studies demonstrated that the p.N88K alteration resulted in significantly reduced co-localization with the acetylcholine receptor (Ohno, 2002; Cossins, 2006). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Fetal akinesia deformation sequence 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Fetal akinesia deformation sequence 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 31, 2023

- -

Myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 05, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.97

L;L;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.1

D;D;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.96

MutPred

0.88

Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);

MVP

0.89

MPC

0.70

ClinPred

0.056

GERP RS

5.1

Varity_R

0.85

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over