NM_005055.5:c.264C>A

Variant names:

• chr11-47448079-G-T
• rs104894299
• NM_005055.5:c.264C>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 18P and 1B. PS1 PS3 PM1 PP5_Very_Strong BP4

The NM_005055.5(RAPSN):​c.264C>A​(p.Asn88Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000221210: Functional studies indicate the Asn88Lys variant results in reduced co-localization with the acetylcholine receptor (AChR) (Cossins 2006)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (1 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:45 O:1
• Conservation: PhyloP100: 5.31
• Publications: 69 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: Pathogenic. The variant received 17 ACMG points.

• PS1: Transcript NM_005055.5 (RAPSN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000221210: Functional studies indicate the Asn88Lys variant results in reduced co-localization with the acetylcholine receptor (AChR) (Cossins 2006).; SCV000372475: Expression studies in HEK cells showed that the p.Asn88Lys variant significantly reduced the recruitment of the acetylcholine receptor to rapsyn clusters (Ohno et al. 2002).; SCV002556391: In vitro functional studies have demonstrated that this variant reduced the recruitment of the acetylcholine receptor (AChR) to rapsyn clusters, as well as impaired postsynaptic morphological development (PMID: 11791205, 16945936) (PS3).; SCV000329485: Published functional studies demonstrate a damaging effect, including diminished coclustering of AChR with rapsyn and impaired post-synaptic morphological development (Ohno et al., 2002; Cossins et al., 2006).; SCV002103767: Experimental evidence evaluating an impact on protein function demonstrated the variant affects the association of rapsyn with AChR and dramatically reduces the stability of AChR clusters (Ohno_2002, Cossins_2006).; SCV000656543: Experimental studies have shown that this missense change affects RAPSN function (PMID: 16945936).; SCV003696773: Functional studies demonstrated that the p.N88K alteration resulted in significantly reduced co-localization with the acetylcholine receptor (Ohno, 2002; Cossins, 2006).; SCV005364025: Functional studies suggest that the p.Asn88Lys variant results in reduced stability of the AChR clusters (Cossins. 2006. PubMed ID: 16945936).; SCV005900555: Functional studies have confirmed this variant leads to reduce co-localization with acetylcholine receptor, leading to a less stable protein (PMID: 16945936).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_005055.5
• PP5: Variant 11-47448079-G-T is Pathogenic according to our data. Variant chr11-47448079-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.112422615). . Strength limited to SUPPORTING due to the PP5.

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.264C>A	p.Asn88Lys	missense	Exon 2 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.264C>A	p.Asn88Lys	missense	Exon 2 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.264C>A	p.Asn88Lys	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.264C>A	p.Asn88Lys	missense	Exon 2 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.264C>A	p.Asn88Lys	missense	Exon 2 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.264C>A	p.Asn88Lys	missense	Exon 2 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 225 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00235

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00156 AC: 391 AN: 250910 AF XY: 0.00141

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00209 AC: 3048 AN: 1461764 Hom.: 1 Cov.: 36 AF XY: 0.00201 AC XY: 1463 AN XY: 727196

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00101 AC: 45 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86258

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53310

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00247 AC: 2742 AN: 1111998

Other (OTH) AF: 0.00199 AC: 120 AN: 60396

GnomAD4 genome AF: 0.00148 AC: 225 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74426

African (AFR) AF: 0.000241 AC: 10 AN: 41524

American (AMR) AF: 0.00242 AC: 37 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00235 AC: 160 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.00160

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00158 AC: 192

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	Congenital myasthenic syndrome 11 (15)
13	-	-	not provided (13)
4	-	-	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (4)
3	-	-	RAPSN-related disorder (3)
2	-	-	Congenital myasthenic syndrome (3)
2	-	-	Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2 (2)
2	-	-	Congenital myasthenic syndrome 4C (2)
1	-	-	Fetal akinesia deformation sequence 1 (1)
1	-	-	Fetal akinesia deformation sequence 2 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	0.97	L
PhyloP100		5.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.88		Gain of ubiquitination at N88 (P = 0.0452)
MVP		0.89
MPC		0.70
ClinPred		0.056	T
GERP RS		5.1
Varity_R		0.85
gMVP		0.79
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs104894299; hg19: chr11-47469631; COSMIC: COSV54085865;