rs104894293

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_005055.5(RAPSN):c.848T>C(p.Leu283Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,609,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L283V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 7.16

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:

LOC124902673 (HGNC:):

LOC124902673 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-47441675-A-G is Pathogenic according to our data. Variant chr11-47441675-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8052.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3, Pathogenic=1}. Variant chr11-47441675-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5 linkuse as main transcript	c.848T>C	p.Leu283Pro	missense_variant	5/8	ENST00000298854.7
LOC124902673	XR_007062669.1 linkuse as main transcript	n.144+3908A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7 linkuse as main transcript	c.848T>C	p.Leu283Pro	missense_variant	5/8	1	NM_005055.5	P1	Q13702-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000406

AC:

AN:

246168

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000801

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

170

AN:

1457538

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

725210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 03, 2020	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 06, 2019	- -

Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Génétique des Maladies du Développement, Hospices Civils de Lyon

Nov 01, 2019

homozygous -

RAPSN-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Jun 29, 2020

This variant has been previously reported as a compound heterozygous change with a splicing variant in one patient with Congenital myasthenic syndrome (CMS, PMID: 16931511). This alteration is located upstream of the coiled-coil region of rapsyn shown to be important for the interaction between rapsyn and acetylcholine receptor (AChR) (PMID: 11791205). In-vitro cotransfection studies using mammalian cells indicated that this variant significantly diminishes coclustering of AChR with rapsyn (PMID: 16931511). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (10/246168) and thus is presumed to be rare. The majority of utilized in-silico tools support a deleterious effect of the c.848T>C (p.Leu283Pro) variant on protein function. Based on the available evidence, the c.848T>C (p.Leu283Pro) variant is classified as Likely Pathogenic. -

Fetal akinesia deformation sequence 2

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 23, 2023

- -

Congenital myasthenic syndrome 11

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 10, 2006

- -

Fetal akinesia deformation sequence 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 24, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 08, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 283 of the RAPSN protein (p.Leu283Pro). This variant is present in population databases (rs104894293, gnomAD 0.008%). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 16931511). ClinVar contains an entry for this variant (Variation ID: 8052). 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 expected to disrupt RAPSN protein function. Experimental studies have shown that this missense change affects RAPSN function (PMID: 16931511). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.21

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;T

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.68

D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

N;N

REVEL

Pathogenic

0.65

Sift

Benign

0.11

T;T

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.10

B;.

Vest4

0.78

MVP

0.93

MPC

0.79

ClinPred

0.27

GERP RS

4.4

Varity_R

0.70

gMVP

0.90

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