rs34312154

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005055.5(RAPSN):c.172C>T(p.Arg58Cys) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,611,616 control chromosomes in the GnomAD database, including 10,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.088 ( 876 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9537 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.51

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028386414).

BP6

Variant 11-47448793-G-A is Benign according to our data. Variant chr11-47448793-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47448793-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5 linkuse as main transcript	c.172C>T	p.Arg58Cys	missense_variant	1/8	ENST00000298854.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7 linkuse as main transcript	c.172C>T	p.Arg58Cys	missense_variant	1/8	1	NM_005055.5	P1	Q13702-1
RAPSN	ENST00000352508.7 linkuse as main transcript	c.172C>T	p.Arg58Cys	missense_variant	1/6	1			Q13702-2
RAPSN	ENST00000529341.1 linkuse as main transcript	c.172C>T	p.Arg58Cys	missense_variant	1/5	1
RAPSN	ENST00000524487.5 linkuse as main transcript	c.172C>T	p.Arg58Cys	missense_variant	1/7	5

Frequencies

GnomAD3 genomes

AF:

0.0884

AC:

13458

AN:

152162

Hom.:

876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0203

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0993

Gnomad ASJ

AF:

0.0861

Gnomad EAS

AF:

0.00519

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.233

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.0724

GnomAD3 exomes

AF:

0.104

AC:

25909

AN:

249460

Hom.:

1749

AF XY:

0.107

AC XY:

14413

AN XY:

135058

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.109

Gnomad ASJ exome

AF:

0.0820

Gnomad EAS exome

AF:

0.00152

Gnomad SAS exome

AF:

0.129

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.106

Gnomad OTH exome

AF:

0.0926

GnomAD4 exome

AF:

0.107

AC:

156705

AN:

1459336

Hom.:

9537

Cov.:

AF XY:

0.108

AC XY:

78523

AN XY:

726112

show subpopulations

Gnomad4 AFR exome

AF:

0.0151

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.0825

Gnomad4 EAS exome

AF:

0.00242

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.210

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.0932

GnomAD4 genome

AF:

0.0884

AC:

13454

AN:

152280

Hom.:

876

Cov.:

AF XY:

0.0950

AC XY:

7077

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0203

Gnomad4 AMR

AF:

0.0991

Gnomad4 ASJ

AF:

0.0861

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.233

Gnomad4 NFE

AF:

0.111

Gnomad4 OTH

AF:

0.0707

Alfa

AF:

0.0962

Hom.:

1258

Bravo

AF:

0.0747

TwinsUK

AF:

0.106

AC:

394

ALSPAC

AF:

0.109

AC:

422

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.107

AC:

918

ExAC

AF:

0.100

AC:

12169

Asia WGS

AF:

0.0470

AC:

164

AN:

3478

EpiCase

AF:

0.0956

EpiControl

AF:

0.0934

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fetal akinesia deformation sequence 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Congenital myasthenic syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Fetal akinesia deformation sequence 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.15

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

D;.;.;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

L;L;.;.

MutationTaster

Benign

0.0000062

P;P;P;P

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;.;P

Vest4

0.36

MPC

0.72

ClinPred

0.038

GERP RS

5.5

Varity_R

0.43

gMVP

0.43

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