rs45547231

Positions:

• chr11-47448165-G-A
• chr11-47448165-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005055.5(RAPSN):​c.193-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,605,420 control chromosomes in the GnomAD database, including 13,838 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1020 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12818 hom.)
• Consequence: RAPSN NM_005055.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.360

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 11-47448165-G-A is Benign according to our data. Variant chr11-47448165-G-A is described in ClinVar as [Benign]. Clinvar id is 259627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47448165-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.193-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000298854.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.193-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.193-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1
RAPSN	ENST00000529341.1	c.193-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1
RAPSN	ENST00000524487.5	c.193-15C>T		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16714 AN: 151986 Hom.: 1018 Cov.: 32

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0853

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0382

Gnomad SAS AF: 0.0541

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.107

GnomAD3 exomes AF: 0.106 AC: 25584 AN: 241002 Hom.: 1579 AF XY: 0.107 AC XY: 14030 AN XY: 131214

Gnomad AFR exome AF: 0.0884

Gnomad AMR exome AF: 0.0565

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.0353

Gnomad SAS exome AF: 0.0606

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.128 AC: 186686 AN: 1453316 Hom.: 12818 Cov.: 36 AF XY: 0.127 AC XY: 91842 AN XY: 723148

Gnomad4 AFR exome AF: 0.0830

Gnomad4 AMR exome AF: 0.0603

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0268

Gnomad4 SAS exome AF: 0.0637

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.110 AC: 16725 AN: 152104 Hom.: 1020 Cov.: 32 AF XY: 0.107 AC XY: 7976 AN XY: 74364

Gnomad4 AFR AF: 0.0840

Gnomad4 AMR AF: 0.0851

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.0383

Gnomad4 SAS AF: 0.0543

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.106

Alfa AF: 0.123 Hom.: 262

Bravo AF: 0.107

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Mar 11, 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. -

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	Mar 06, 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

Mar 06, 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
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.2
DANN	Benign	0.84

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: rs45547231; hg19: chr11-47469717; COSMIC: COSV54085037;