rs7111873

chr11-47447887-A-Gchr11-47447887-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005055.5(RAPSN):c.456T>C(p.Tyr152=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.698 in 1,612,224 control chromosomes in the GnomAD database, including 397,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31209 hom., cov: 31)
  • Exomes 𝑓: 0.71 (366575 hom.)
• Consequence: RAPSN NM_005055.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.05

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-47447887-A-G is Benign according to our data. Variant chr11-47447887-A-G is described in ClinVar as [Benign]. Clinvar id is 130091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47447887-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.456T>C	p.Tyr152=	synonymous_variant	2/8	ENST00000298854.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.456T>C	p.Tyr152=	synonymous_variant	2/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.456T>C	p.Tyr152=	synonymous_variant	2/6	1
RAPSN	ENST00000529341.1	c.456T>C	p.Tyr152=	synonymous_variant	2/5	1
RAPSN	ENST00000524487.5	c.456T>C	p.Tyr152=	synonymous_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.626 AC: 95043 AN: 151872 Hom.: 31192 Cov.: 31

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.685

GnomAD3 exomes AF: 0.680 AC: 168439 AN: 247528 Hom.: 58478 AF XY: 0.694 AC XY: 93159 AN XY: 134156

Gnomad AFR exome AF: 0.414

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.720

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.779

Gnomad FIN exome AF: 0.619

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.722

GnomAD4 exome AF: 0.706 AC: 1030270 AN: 1460234 Hom.: 366575 Cov.: 85 AF XY: 0.709 AC XY: 515005 AN XY: 726378

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.601

Gnomad4 SAS exome AF: 0.770

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.719

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.626 AC: 95101 AN: 151990 Hom.: 31209 Cov.: 31 AF XY: 0.624 AC XY: 46332 AN XY: 74306

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.660

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.606

Gnomad4 NFE AF: 0.721

Gnomad4 OTH AF: 0.689

Alfa AF: 0.699 Hom.: 22867

Bravo AF: 0.618

Asia WGS AF: 0.720 AC: 2509 AN: 3478

EpiCase AF: 0.736

EpiControl AF: 0.737

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2015	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. -

Congenital myasthenic syndrome 11 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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

- -

Fetal akinesia deformation sequence 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Congenital myasthenic syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.016
Dann	Benign	0.41

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

Other links and lift over

dbSNP: rs7111873; hg19: chr11-47469439; COSMIC: COSV54084050;