rs7126210

Positions:

• chr11-47438755-A-G

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.1143T>C​(p.Pro381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,562,730 control chromosomes in the GnomAD database, including 382,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (31106 hom., cov: 32)
  • Exomes 𝑓: 0.70 (351469 hom.)
• Consequence: RAPSN NM_005055.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.206

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 11-47438755-A-G is Benign according to our data. Variant chr11-47438755-A-G is described in ClinVar as [Benign]. Clinvar id is 130089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47438755-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.206 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.1143T>C	p.Pro381=	synonymous_variant	7/8	ENST00000298854.7	NP_005046.2
LOC124902673	XR_007062669.1	n.144+988A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.1143T>C	p.Pro381=	synonymous_variant	7/8	1	NM_005055.5	ENSP00000298854	P1

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94917 AN: 151888 Hom.: 31092 Cov.: 32

Gnomad AFR AF: 0.418

Gnomad AMI AF: 0.868

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.684

GnomAD3 exomes AF: 0.664 AC: 121435 AN: 182762 Hom.: 41338 AF XY: 0.678 AC XY: 65901 AN XY: 97248

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.623

Gnomad SAS exome AF: 0.773

Gnomad FIN exome AF: 0.611

Gnomad NFE exome AF: 0.704

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.703 AC: 991432 AN: 1410724 Hom.: 351469 Cov.: 75 AF XY: 0.706 AC XY: 491249 AN XY: 695834

Gnomad4 AFR exome AF: 0.407

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.593

Gnomad4 SAS exome AF: 0.768

Gnomad4 FIN exome AF: 0.623

Gnomad4 NFE exome AF: 0.717

Gnomad4 OTH exome AF: 0.707

GnomAD4 genome AF: 0.625 AC: 94972 AN: 152006 Hom.: 31106 Cov.: 32 AF XY: 0.623 AC XY: 46278 AN XY: 74314

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.669

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.658

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.607

Gnomad4 NFE AF: 0.720

Gnomad4 OTH AF: 0.688

Alfa AF: 0.711 Hom.: 59455

Bravo AF: 0.617

Asia WGS AF: 0.720 AC: 2508 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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	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	Jul 10, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.62
CADD	Benign	6.6
DANN	Benign	0.77

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: rs7126210; hg19: chr11-47460306; COSMIC: COSV54083844;