rs886037842

Variant names:

• chr11-47449163-G-C
• rs886037842
• ENST00000949301.1:c.-199C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-47449163-G-C
• chr11-47449163-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The ENST00000949301.1(RAPSN):​c.-199C>G variant causes a 5 prime UTR 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 (★★). ClinVar reports functional evidence for this variant: "SCV004099524: A luciferase reporter assay showed that the variant reduces transcriptional activity (Ohno_2003). PMID:12651869" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAPSN ENST00000949301.1 5_prime_UTR
• 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), 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: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004099524: A luciferase reporter assay showed that the variant reduces transcriptional activity (Ohno_2003). PMID: 12651869; SCV001387197: Studies have shown that this variant alters RAPSN gene expression (PMID: 12651869).
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000949301.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPSN	NM_005055.5	MANE Select	c.-199C>G		upstream_gene	N/A	NP_005046.2
	RAPSN	NM_001440490.1		c.-199C>G		upstream_gene	N/A	NP_001427419.1
	RAPSN	NM_001440491.1		c.-199C>G		upstream_gene	N/A	NP_001427420.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPSN	ENST00000949301.1		c.-199C>G		5_prime_UTR	Exon 1 of 8	ENSP00000619360.1
	RAPSN	ENST00000897203.1		c.-199C>G		5_prime_UTR	Exon 1 of 7	ENSP00000567262.1
	RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.-199C>G		upstream_gene	N/A	ENSP00000298854.2	Q13702-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 6

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myasthenic syndrome (2)
1	-	-	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (1)
1	-	-	Fetal akinesia deformation sequence 2 (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886037842;

hg19: chr11-47470715;