rs121909255

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000298854.7(RAPSN):​c.484G>A​(p.Glu162Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,322 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

RAPSN
ENST00000298854.7 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 3 uncertain in ENST00000298854.7
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 11-47447859-C-T is Pathogenic according to our data. Variant chr11-47447859-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47447859-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RAPSNNM_005055.5 linkuse as main transcriptc.484G>A p.Glu162Lys missense_variant 2/8 ENST00000298854.7 NP_005046.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RAPSNENST00000298854.7 linkuse as main transcriptc.484G>A p.Glu162Lys missense_variant 2/81 NM_005055.5 ENSP00000298854 P1Q13702-1
RAPSNENST00000352508.7 linkuse as main transcriptc.484G>A p.Glu162Lys missense_variant 2/61 ENSP00000298853 Q13702-2
RAPSNENST00000529341.1 linkuse as main transcriptc.484G>A p.Glu162Lys missense_variant 2/51 ENSP00000431732
RAPSNENST00000524487.5 linkuse as main transcriptc.484G>A p.Glu162Lys missense_variant 2/75 ENSP00000435551

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000242
AC:
6
AN:
248044
Hom.:
0
AF XY:
0.0000372
AC XY:
5
AN XY:
134550
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000164
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000179
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461134
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
726848
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000594

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2023This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 162 of the RAPSN protein (p.Glu162Lys). This variant is present in population databases (rs121909255, gnomAD 0.02%). This missense change has been observed in individual(s) with fetal akinesia deformation sequence, arthrogryposis multiplex congenita, and congenital myasthenic syndrome (PMID: 17594401, 26147564, 26910802, 28495245). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 8056). 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: 17594401). For these reasons, this variant has been classified as Pathogenic. -
Fetal akinesia deformation sequence 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 01, 2024- -
Congenital myasthenic syndrome 11 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.39
T;.;.;.
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.97
D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Uncertain
2.4
M;M;.;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Pathogenic
0.83
D
PROVEAN
Uncertain
-3.4
D;D;D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D
Polyphen
0.62
P;P;.;D
Vest4
0.96
MutPred
0.93
Gain of methylation at E162 (P = 0.0127);Gain of methylation at E162 (P = 0.0127);Gain of methylation at E162 (P = 0.0127);Gain of methylation at E162 (P = 0.0127);
MVP
0.94
MPC
0.63
ClinPred
0.97
D
GERP RS
5.1
Varity_R
0.85
gMVP
0.81

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.

Other links and lift over

dbSNP: rs121909255; hg19: chr11-47469411; API