rs34312154

Variant names:

• chr11-47448793-G-A
• rs34312154
• NM_005055.5:c.172C>T
• RAPSN p.Arg58Cys

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005055.5(RAPSN):​c.172C>T​(p.Arg58Cys) variant causes a missense change. The variant allele was found at a frequency of 0.106 in 1,611,616 control chromosomes in the GnomAD database, including 10,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R58H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.088 (876 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9537 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.51
• Publications: 28 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028386414).
• BP6: Variant 11-47448793-G-A is Benign according to our data. Variant chr11-47448793-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

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.172C>T	p.Arg58Cys	missense	Exon 1 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.172C>T	p.Arg58Cys	missense	Exon 1 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.172C>T	p.Arg58Cys	missense	Exon 1 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.172C>T	p.Arg58Cys	missense	Exon 1 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.172C>T	p.Arg58Cys	missense	Exon 1 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.172C>T	p.Arg58Cys	missense	Exon 1 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes AF: 0.0884 AC: 13458 AN: 152162 Hom.: 876 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0993

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0724

GnomAD2 exomes AF: 0.104 AC: 25909 AN: 249460 AF XY: 0.107

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.109

Gnomad ASJ exome AF: 0.0820

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.0926

GnomAD4 exome AF: 0.107 AC: 156705 AN: 1459336 Hom.: 9537 Cov.: 32 AF XY: 0.108 AC XY: 78523 AN XY: 726112

African (AFR) AF: 0.0151 AC: 505 AN: 33476

American (AMR) AF: 0.109 AC: 4894 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 2155 AN: 26136

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39696

South Asian (SAS) AF: 0.133 AC: 11491 AN: 86256

European-Finnish (FIN) AF: 0.210 AC: 10683 AN: 50956

Middle Eastern (MID) AF: 0.0848 AC: 489 AN: 5768

European-Non Finnish (NFE) AF: 0.109 AC: 120765 AN: 1111958

Other (OTH) AF: 0.0932 AC: 5627 AN: 60372

GnomAD4 genome AF: 0.0884 AC: 13454 AN: 152280 Hom.: 876 Cov.: 32 AF XY: 0.0950 AC XY: 7077 AN XY: 74470

African (AFR) AF: 0.0203 AC: 842 AN: 41568

American (AMR) AF: 0.0991 AC: 1516 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.114 AC: 552 AN: 4830

European-Finnish (FIN) AF: 0.233 AC: 2469 AN: 10608

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7534 AN: 68010

Other (OTH) AF: 0.0707 AC: 149 AN: 2108

Alfa AF: 0.0955 Hom.: 2724

Bravo AF: 0.0747

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.0956

EpiControl AF: 0.0934

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Congenital myasthenic syndrome 11 (2)
-	-	1	Congenital myasthenic syndrome (1)
-	-	1	Fetal akinesia deformation sequence 1 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (1)
-	-	1	Fetal akinesia deformation sequence 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
PromoterAI		-0.0038	Neutral
Varity_R		0.43
gMVP		0.43
Mutation Taster		=94/6	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34312154;

hg19: chr11-47470345;

COSMIC: COSV54085305;