rs1377574572

Positions:

• chr11-47442684-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005055.5(RAPSN):​c.662G>A​(p.Arg221His) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.72

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18309295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.662G>A	p.Arg221His	missense_variant	3/8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.662G>A	p.Arg221His	missense_variant	3/8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.662G>A	p.Arg221His	missense_variant	3/6	1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.662G>A	p.Arg221His	missense_variant	3/5	1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.532-763G>A		intron_variant		5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250878 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135668

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461872 Hom.: 0 Cov.: 34 AF XY: 0.0000151 AC XY: 11 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 221 of the RAPSN protein (p.Arg221His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAPSN-related conditions. ClinVar contains an entry for this variant (Variation ID: 476124). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Congenital myasthenic syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Feb 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.41	T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.34	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.71	N;N;N
REVEL	Benign	0.084
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.18
MutPred		0.41		Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);Loss of MoRF binding (P = 0.0174);
MVP		0.85
MPC		0.20
ClinPred		0.49	T
GERP RS		5.1
Varity_R		0.076
gMVP		0.20

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: rs1377574572; hg19: chr11-47464236;