chr11-47449163-G-C

Variant names:

• chr11-47449163-G-C
• rs886037842
• NM_005055.5:c.-199C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_005055.5(RAPSN):​c.-199C>G variant causes a upstream gene change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAPSN NM_005055.5 upstream_gene
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 4.40
• Publications: 0 publications found

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]

RAPSN Gene-Disease associations (from GenCC):

• fetal akinesia deformation sequence 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• neuromuscular disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• congenital myasthenic syndrome 11

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47449163-G-C is Pathogenic according to our data. Variant chr11-47449163-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 264677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.-199C>G		upstream_gene_variant		ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.-199C>G		upstream_gene_variant		1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.-199C>G		upstream_gene_variant		1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.-199C>G		upstream_gene_variant		1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.-199C>G		upstream_gene_variant		5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome Pathogenic:1 Other:1

Sep 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAPSN c.-199C>G (also known as -27C>G) is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 31408 control chromosomes (gnomAD). c.-199C>G has been reported as a biallelic genotype in the literature in individuals affected with Congenital Myasthenic Syndrome (Ohno_2003, Milone_2009). These data indicate that the variant may be associated with disease. A luciferase reporter assay showed that the variant reduces transcriptional activity (Ohno_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12651869, 19620612). One ClinVar submitter has assessed the variant since 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Aug 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as -27C>G. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters RAPSN gene expression (PMID: 12651869). ClinVar contains an entry for this variant (Variation ID: 264677). This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 12651869, 14729848, 19620612). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant occurs in a non-coding region of the RAPSN gene. It does not change the encoded amino acid sequence of the RAPSN protein.

Fetal akinesia deformation sequence 2 Pathogenic:1

Aug 24, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Benign	0.91
PhyloP100		4.4
PromoterAI		-0.074	Neutral
Mutation Taster		=109/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037842; hg19: chr11-47470715;