rs529117281
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005055.5(RAPSN):c.1036C>T(p.Arg346Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000453 in 1,567,862 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R346P) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000048 ( 1 hom. )
Consequence
RAPSN
NM_005055.5 missense
NM_005055.5 missense
Scores
5
12
2
Clinical Significance
Conservation
PhyloP100: 4.03
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAPSN | NM_005055.5 | c.1036C>T | p.Arg346Trp | missense_variant | 7/8 | ENST00000298854.7 | |
LOC124902673 | XR_007062669.1 | n.144+1095G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAPSN | ENST00000298854.7 | c.1036C>T | p.Arg346Trp | missense_variant | 7/8 | 1 | NM_005055.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000135 AC: 24AN: 177166Hom.: 0 AF XY: 0.000191 AC XY: 18AN XY: 94062
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GnomAD4 exome AF: 0.0000480 AC: 68AN: 1415556Hom.: 1 Cov.: 34 AF XY: 0.0000657 AC XY: 46AN XY: 699628
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152306Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74460
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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 | Apr 13, 2022 | - - |
Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 346 of the RAPSN protein (p.Arg346Trp). This variant is present in population databases (rs529117281, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. ClinVar contains an entry for this variant (Variation ID: 542734). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. | Apr 13, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.;.;.
MutationTaster
Benign
D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D
Sift4G
Uncertain
D;D;D;D
Polyphen
D;D;.;D
Vest4
MutPred
Loss of disorder (P = 0.0206);.;.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
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