rs747627949
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_005055.5(RAPSN):c.59A>T(p.Asn20Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,206 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Consequence
RAPSN
NM_005055.5 missense
NM_005055.5 missense
Scores
7
9
3
Clinical Significance
Conservation
PhyloP100: 7.67
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a repeat TPR 1 (size 33) in uniprot entity RAPSN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005055.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.89
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAPSN | NM_005055.5 | c.59A>T | p.Asn20Ile | missense_variant | 1/8 | ENST00000298854.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAPSN | ENST00000298854.7 | c.59A>T | p.Asn20Ile | missense_variant | 1/8 | 1 | NM_005055.5 | P1 | |
RAPSN | ENST00000352508.7 | c.59A>T | p.Asn20Ile | missense_variant | 1/6 | 1 | |||
RAPSN | ENST00000529341.1 | c.59A>T | p.Asn20Ile | missense_variant | 1/5 | 1 | |||
RAPSN | ENST00000524487.5 | c.59A>T | p.Asn20Ile | missense_variant | 1/7 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251474Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135918
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GnomAD4 exome Cov.: 32
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74358
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 09, 2019 | - - |
Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces asparagine with isoleucine at codon 20 of the RAPSN protein (p.Asn20Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs747627949, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Congenital myasthenic syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;D
Vest4
MutPred
Loss of disorder (P = 0.0239);Loss of disorder (P = 0.0239);Loss of disorder (P = 0.0239);Loss of disorder (P = 0.0239);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at