11-47438007-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005055.5(RAPSN):c.1207C>T(p.Arg403Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000286 in 1,398,110 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

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]

LOC124902673 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.1207C>T	p.Arg403Cys	missense_variant	8/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.144+240G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.1207C>T	p.Arg403Cys	missense_variant	8/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.1030C>T	p.Arg344Cys	missense_variant	6/6	1
RAPSN	ENST00000524487.5	c.1048C>T	p.Arg350Cys	missense_variant	7/7	5
RAPSN	ENST00000528356.1	n.162C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000640 AC: 1 AN: 156278 Hom.: 0 AF XY: 0.0000122 AC XY: 1 AN XY: 82238

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: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1398110 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689548

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: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2021

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 403 of the RAPSN protein (p.Arg403Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Uncertain	0.047	D
MutationAssessor	Pathogenic	3.9	H;.;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N;N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.22
MutPred		0.38		Loss of MoRF binding (P = 0.0115);.;.;
MVP		0.80
MPC		0.72
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.68

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

LitVar

Other links and lift over

dbSNP: rs1165174416; hg19: chr11-47459558;