11-47438832-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005055.5(RAPSN):c.1066G>A(p.Val356Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,573,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 7.50

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

fetal akinesia deformation sequence 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
neuromuscular disease
Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
congenital myasthenic syndrome 11
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
fetal akinesia deformation sequence 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RAPSN links:

LOC124902673 (HGNC:):

LOC124902673 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAPSN	NM_005055.5	MANE Select	c.1066G>A	p.Val356Met	missense	Exon 7 of 8	NP_005046.2
RAPSN	NM_001440490.1		c.1202G>A	p.Arg401His	missense	Exon 7 of 8	NP_001427419.1
RAPSN	NM_001440491.1		c.1151G>A	p.Arg384His	missense	Exon 7 of 8	NP_001427420.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.1066G>A	p.Val356Met	missense	Exon 7 of 8	ENSP00000298854.2
RAPSN	ENST00000352508.7	TSL:1	c.889G>A	p.Val297Met	missense	Exon 5 of 6	ENSP00000298853.3
RAPSN	ENST00000529341.1	TSL:1	c.889G>A	p.Val297Met	missense	Exon 5 of 5	ENSP00000431732.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000537

AC:

AN:

186296

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000699

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000103

Gnomad OTH exome

AF:

0.000206

GnomAD4 exome

AF:

0.000148

AC:

210

AN:

1421388

Hom.:

Cov.:

AF XY:

0.000156

AC XY:

110

AN XY:

702986

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32900

American (AMR)

AF:

0.0000258

AC:

AN:

38728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25328

East Asian (EAS)

AF:

0.0000264

AC:

AN:

37912

South Asian (SAS)

AF:

0.0000495

AC:

AN:

80870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50390

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000179

AC:

195

AN:

1090680

Other (OTH)

AF:

0.000119

AC:

AN:

58866

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000419

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 03, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1066G>A (p.V356M) alteration is located in exon 7 (coding exon 7) of the RAPSN gene. This alteration results from a G to A substitution at nucleotide position 1066, causing the valine (V) at amino acid position 356 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2

Uncertain:1

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Fetal akinesia deformation sequence 1

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not provided

Uncertain:1

May 19, 2025

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 356 of the RAPSN protein (p.Val356Met). This variant is present in population databases (rs570140663, gnomAD 0.01%). 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: 304970). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAPSN protein function with a negative predictive value of 95%. 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

Apr 13, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Congenital myasthenic syndrome 11

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.080

PhyloP100

7.5

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.18

REVEL

Benign

0.16

Sift

Benign

0.43

Sift4G

Benign

0.19

Polyphen

0.073

Vest4

0.77

MVP

0.66

MPC

0.16

ClinPred

0.16

GERP RS

5.8

Varity_R

0.15

gMVP

0.58

Mutation Taster

=50/50

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over