rs45603036

chr11-47441668-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005055.5(RAPSN):c.855G>A(p.Gln285=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,609,464 control chromosomes in the GnomAD database, including 13,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (972 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12957 hom.)
• Consequence: RAPSN NM_005055.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.92

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]

LOC124902673 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-47441668-C-T is Benign according to our data. Variant chr11-47441668-C-T is described in ClinVar as [Benign]. Clinvar id is 130092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47441668-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.855G>A	p.Gln285=	synonymous_variant	5/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.144+3901C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.855G>A	p.Gln285=	synonymous_variant	5/8	1	NM_005055.5	P1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16025 AN: 152132 Hom.: 972 Cov.: 32

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0540

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.103

GnomAD3 exomes AF: 0.105 AC: 25850 AN: 245276 Hom.: 1604 AF XY: 0.107 AC XY: 14208 AN XY: 133232

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0568

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0356

Gnomad SAS exome AF: 0.0602

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.129 AC: 187755 AN: 1457214 Hom.: 12957 Cov.: 33 AF XY: 0.127 AC XY: 92385 AN XY: 725022

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.0606

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.0635

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.105 AC: 16027 AN: 152250 Hom.: 972 Cov.: 32 AF XY: 0.103 AC XY: 7655 AN XY: 74436

Gnomad4 AFR AF: 0.0639

Gnomad4 AMR AF: 0.0879

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.0379

Gnomad4 SAS AF: 0.0542

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.102

Alfa AF: 0.126 Hom.: 617

Bravo AF: 0.102

Asia WGS AF: 0.0600 AC: 207 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.145

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital myasthenic syndrome 11 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

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

Invitae

Feb 01, 2024

- -

Fetal akinesia deformation sequence 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 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	-0.45
Cadd	Benign	8.2
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45603036; hg19: chr11-47463220; COSMIC: COSV54085857;