11-47447853-G-C

Position:

• chr11-47447853-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_005055.5(RAPSN):​c.490C>G​(p.Arg164Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.53

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a repeat TPR 4 (size 33) in uniprot entity RAPSN_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-47447853-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871
• PP5: Variant 11-47447853-G-C is Pathogenic according to our data. Variant chr11-47447853-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1417647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.490C>G	p.Arg164Gly	missense_variant	2/8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.490C>G	p.Arg164Gly	missense_variant	2/8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.490C>G	p.Arg164Gly	missense_variant	2/6	1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.490C>G	p.Arg164Gly	missense_variant	2/5	1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.490C>G	p.Arg164Gly	missense_variant	2/7	5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg164 amino acid residue in RAPSN. Other variant(s) that disrupt this residue have been observed in individuals with RAPSN-related conditions (PMID: 16931511, 19620612, 27966543, 32070632), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAPSN protein function. ClinVar contains an entry for this variant (Variation ID: 1417647). This missense change has been observed in individual(s) with clinical features of congenital myasthenic syndrome (Invitae). 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 sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 164 of the RAPSN protein (p.Arg164Gly). -

Congenital myasthenic syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Oct 25, 2024

Variant summary: RAPSN c.490C>G (p.Arg164Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 247670 control chromosomes. c.490C>G has been reported in the literature in a compound heterozygous individual affected with Congenital Myasthenic Syndrome (Estephan_2022). This variant has also been observed in compound heterozygous individual(s) with Congenital Myasthenic Syndrome. In addition, a different amino acid change at the same codon (c.490C>T, p.Arg164Cys) has been reported in multiple individuals with Congenital Myasthenic Syndrome (PMID: 16931511, 32070632, 32528171, 34106991). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34749429, Invitae). ClinVar contains an entry for this variant (Variation ID: 1417647). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.90	L;L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Benign	0.083	T;T;D;T
Polyphen		0.80	P;B;.;D
Vest4		0.84
MutPred		0.77		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.86
MPC		0.60
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.60

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47469405;