11-47448165-G-T

Position:

• chr11-47448165-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_005055.5(RAPSN):​c.193-15C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAPSN NM_005055.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: -0.360

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47448165-G-T is Pathogenic according to our data. Variant chr11-47448165-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 8053.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr11-47448165-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.193-15C>A		intron_variant		ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.193-15C>A		intron_variant		1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.193-15C>A		intron_variant		1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.193-15C>A		intron_variant		1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.193-15C>A		intron_variant		5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000415 AC: 1 AN: 241002 Hom.: 0 AF XY: 0.00000762 AC XY: 1 AN XY: 131214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000911

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453396 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 723176

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000309 Hom.: 262

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Aug 08, 2024

Variant summary: RAPSN c.193-15C>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. Three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Miller_2006). The variant allele was found at a frequency of 4.1e-06 in 241002 control chromosomes. c.193-15C>A has been reported in the literature in individuals affected with Congenital Myasthenic Syndrome (Krenn_2023, Miller_2006). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36308527, 16931511). ClinVar contains an entry for this variant (Variation ID: 8053). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Congenital myasthenic syndrome 11 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 10, 2006

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 02, 2021

This sequence change falls in intron 1 of the RAPSN gene. It does not directly change the encoded amino acid sequence of the RAPSN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 16931511). This variant is also known as IVS1-15C>A. ClinVar contains an entry for this variant (Variation ID: 8053). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 16931511). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.95		Position offset: -2
DS_AL_spliceai		0.34		Position offset: -15

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

Publications

LitVar

Other links and lift over

dbSNP: rs45547231; hg19: chr11-47469717;