rs1377574572

Variant names:

• chr11-47442684-C-T
• rs1377574572
• NM_005055.5:c.662G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R221C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.72
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P
• 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

LOC124902673 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18309295).
• BP6: Variant 11-47442684-C-T is Benign according to our data. Variant chr11-47442684-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476124.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005055.5. 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.662G>A	p.Arg221His	missense	Exon 3 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.662G>A	p.Arg221His	missense	Exon 3 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.662G>A	p.Arg221His	missense	Exon 3 of 8	NP_001427420.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.662G>A	p.Arg221His	missense	Exon 3 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.662G>A	p.Arg221His	missense	Exon 3 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.662G>A	p.Arg221His	missense	Exon 3 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250878 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.00000629 AC: 7 AN: 1112008

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome (1)
-	1	-	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.084
Sift	Benign	0.58	T
Sift4G	Benign	0.48	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.41		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
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs1377574572; hg19: chr11-47464236;