Genetic Variant NM_005055.5:c.264C>A (chr11-47448079-G-T) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS1PM1PP5_Very_StrongBP4

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 (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:45O:1

Conservation

PhyloP100: 5.31

Publications

68 publications found

Variant links:

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

RAPSN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS1

Transcript NM_005055.5 (RAPSN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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

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.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00201

AC XY:

1463

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.00101

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000638

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000450

AC:

AN:

53310

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00247

AC:

2742

AN:

1111998

Other (OTH)

AF:

0.00199

AC:

120

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

205

410

616

821

1026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00148

AC:

225

AN:

152228

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41524

American (AMR)

AF:

0.00242

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00160

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00185

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myasthenic syndrome 11 (15)

not provided (13)

Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (4)

RAPSN-related disorder (3)

Congenital myasthenic syndrome (3)

Congenital myasthenic syndrome 11;C4760576:Fetal akinesia deformation sequence 2 (2)

Congenital myasthenic syndrome 4C (2)

Fetal akinesia deformation sequence 1 (1)

Fetal akinesia deformation sequence 2 (1)

Inborn genetic diseases (1)

Myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.11

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.97

PhyloP100

5.3

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.88

Gain of ubiquitination at N88 (P = 0.0452)

MVP

0.89

MPC

0.70

ClinPred

0.056

GERP RS

5.1

Varity_R

0.85

gMVP

0.79

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over