chr11-47449174-T-C

Variant names:

• chr11-47449174-T-C
• rs786200905
• ENST00000949301.1:c.-210A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The ENST00000949301.1(RAPSN):​c.-210A>G variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.0000183 in 656,818 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000939948: Studies have shown that this variant alters RAPSN gene expression (PMID:12651869, 15282317).".

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RAPSN ENST00000949301.1 5_prime_UTR
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:2
• Conservation: PhyloP100: 4.80
• Publications: 2 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 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000939948: Studies have shown that this variant alters RAPSN gene expression (PMID: 12651869, 15282317).
• PP5: Variant 11-47449174-T-C is Pathogenic according to our data. Variant chr11-47449174-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29). . 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.-210A>G		upstream_gene	N/A	NP_005046.2
	RAPSN	NM_001440490.1		c.-210A>G		upstream_gene	N/A	NP_001427419.1
	RAPSN	NM_001440491.1		c.-210A>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.-210A>G		5_prime_UTR	Exon 1 of 8	ENSP00000619360.1
	RAPSN	ENST00000897203.1		c.-210A>G		5_prime_UTR	Exon 1 of 7	ENSP00000567262.1
	RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.-210A>G		upstream_gene	N/A	ENSP00000298854.2	Q13702-1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 9 AN: 504574 Hom.: 0 Cov.: 5 AF XY: 0.0000149 AC XY: 4 AN XY: 267610

African (AFR) AF: 0.00 AC: 0 AN: 14526

American (AMR) AF: 0.0000698 AC: 2 AN: 28646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15776

East Asian (EAS) AF: 0.00 AC: 0 AN: 31452

South Asian (SAS) AF: 0.0000193 AC: 1 AN: 51832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30340

Middle Eastern (MID) AF: 0.00185 AC: 4 AN: 2164

European-Non Finnish (NFE) AF: 0.00000663 AC: 2 AN: 301634

Other (OTH) AF: 0.00 AC: 0 AN: 28204

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital myasthenic syndrome 11 (2)
2	-	-	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	Congenital myasthenic syndrome (2)
1	-	-	Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2 (2)
1	-	-	Fetal akinesia deformation sequence 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.92
PhyloP100		4.8
PromoterAI		0.30	Neutral
Mutation Taster		=300/0	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: rs786200905;

hg19: chr11-47470726;