NM_005055.5:c.524A>G

Variant names:

• chr11-47447819-T-C
• rs863224912
• NM_005055.5:c.524A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005055.5(RAPSN):​c.524A>G​(p.Gln175Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,670 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 no classification for the single variant (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.46
• Publications: 0 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31692308).

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.524A>G	p.Gln175Arg	missense	Exon 2 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.524A>G	p.Gln175Arg	missense	Exon 2 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.524A>G	p.Gln175Arg	missense	Exon 2 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.524A>G	p.Gln175Arg	missense	Exon 2 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.524A>G	p.Gln175Arg	missense	Exon 2 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.524A>G	p.Gln175Arg	missense	Exon 2 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459670 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726020

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 85908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52880

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111222

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 32

Alfa AF: 0.000167 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.81
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.027
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.90	L
PhyloP100		4.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.10
Sift	Benign	0.91	T
Sift4G	Benign	0.25	T
Polyphen		0.035	B
Vest4		0.52
MutPred		0.46		Loss of methylation at K177 (P = 0.058)
MVP		0.76
MPC		0.44
ClinPred		0.73	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.46
Mutation Taster		=13/87	disease causing

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: rs863224912; hg19: chr11-47469371;