rs786200904

Positions:

• chr11-47442792-A-AAGAAC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005055.5(RAPSN):​c.553_554insGTTCT​(p.Phe185CysfsTer20) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RAPSN NM_005055.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.87

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47442792-A-AAGAAC is Pathogenic according to our data. Variant chr11-47442792-A-AAGAAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.553_554insGTTCT	p.Phe185CysfsTer20	frameshift_variant	3/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.145-4532_145-4528dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.553_554insGTTCT	p.Phe185CysfsTer20	frameshift_variant	3/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.553_554insGTTCT	p.Phe185CysfsTer20	frameshift_variant	3/6	1
RAPSN	ENST00000529341.1	c.553_554insGTTCT	p.Phe185CysfsTer20	frameshift_variant	3/5	1
RAPSN	ENST00000524487.5	c.532-872_532-871insGTTCT		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.0000110 AC XY: 8 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RAPSN-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 15, 2022

The RAPSN c.549_553dup5 variant is predicted to result in a frameshift and premature protein termination (p.Phe185Cysfs*20). This variant was reported in the compound heterozygous state in patients with congenital myasthenic syndrome (variant referred to as 553ins5 in Patient 4, Ohno et al. 2002. PubMed ID: 11791205; variant referred to as 551ins5 in patients 2 and 5, Burke et al. 2003. PubMed ID: 14504330). Functional analysis showed that this variant impacted recruitment of the acetylcholine receptor to rapsyn clusters (Ohno et al. 2002. PubMed ID: 11791205). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in RAPSN are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2022

This premature translational stop signal has been observed in individual(s) with congenital myasthenic syndrome (PMID: 11791205). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this premature translational stop signal affects RAPSN function (PMID: 11791205). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 8048). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe185Cysfs*20) in the RAPSN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAPSN are known to be pathogenic (PMID: 17686188). -

Fetal akinesia deformation sequence 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 10, 2024

- -

Congenital myasthenic syndrome 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786200904; hg19: chr11-47464344;