rs57878668

Positions:

chr11-47448102-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005055.5(RAPSN):c.241T>C(p.Phe81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00569 in 1,613,790 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 47 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 84 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.92

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=0.006080568).

BP6

Variant 11-47448102-A-G is Benign according to our data. Variant chr11-47448102-A-G is described in ClinVar as [Benign]. Clinvar id is 235304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47448102-A-G is described in Lovd as [Likely_benign]. Variant chr11-47448102-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0173 (2625/152168) while in subpopulation AFR AF= 0.0481 (1996/41500). AF 95% confidence interval is 0.0463. There are 47 homozygotes in gnomad4. There are 1290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5 linkuse as main transcript	c.241T>C	p.Phe81Leu	missense_variant	2/8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7 linkuse as main transcript	c.241T>C	p.Phe81Leu	missense_variant	2/8	1	NM_005055.5	ENSP00000298854	P1	Q13702-1
RAPSN	ENST00000352508.7 linkuse as main transcript	c.241T>C	p.Phe81Leu	missense_variant	2/6	1		ENSP00000298853		Q13702-2
RAPSN	ENST00000529341.1 linkuse as main transcript	c.241T>C	p.Phe81Leu	missense_variant	2/5	1		ENSP00000431732
RAPSN	ENST00000524487.5 linkuse as main transcript	c.241T>C	p.Phe81Leu	missense_variant	2/7	5		ENSP00000435551

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2621

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0149

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00518

Gnomad OTH

AF:

0.0106

GnomAD3 exomes

AF:

0.00786

AC:

1969

AN:

250414

Hom.:

AF XY:

0.00686

AC XY:

929

AN XY:

135476

show subpopulations

Gnomad AFR exome

AF:

0.0499

Gnomad AMR exome

AF:

0.00382

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.0133

Gnomad NFE exome

AF:

0.00575

Gnomad OTH exome

AF:

0.00670

GnomAD4 exome

AF:

0.00448

AC:

6552

AN:

1461622

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

3179

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0491

Gnomad4 AMR exome

AF:

0.00396

Gnomad4 ASJ exome

AF:

0.00310

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000719

Gnomad4 FIN exome

AF:

0.0128

Gnomad4 NFE exome

AF:

0.00311

Gnomad4 OTH exome

AF:

0.00651

GnomAD4 genome

AF:

0.0173

AC:

2625

AN:

152168

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1290

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0481

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.0149

Gnomad4 NFE

AF:

0.00518

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00691

Hom.:

Bravo

AF:

0.0173

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0518

AC:

228

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00912

AC:

1107

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00379

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fetal akinesia deformation sequence 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Congenital myasthenic syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 13, 2021

- -

Congenital myasthenic syndrome 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.046

T;.;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.015

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;T;T

MetaRNN

Benign

0.0061

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.47

N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.48

T;T;T;T

Sift4G

Benign

0.51

T;T;T;T

Polyphen

0.0030

B;B;.;B

Vest4

0.24

MutPred

0.14

Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);

MVP

0.78

MPC

0.18

ClinPred

0.015

GERP RS

4.8

Varity_R

0.16

gMVP

0.37

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