Genetic Variant NM_005055.5:c.59A>G (chr11-47448906-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_005055.5(RAPSN):c.59A>G(p.Asn20Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N20I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RAPSN
NM_005055.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a repeat TPR 1 (size 33) in uniprot entity RAPSN_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_005055.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5 link	c.59A>G	p.Asn20Ser	missense_variant	Exon 1 of 8	ENST00000298854.7	NP_005046.2	Q13702-1A0A0S2Z4F8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAPSN	ENST00000298854.7 link	c.59A>G	p.Asn20Ser	missense_variant	Exon 1 of 8	1	NM_005055.5	ENSP00000298854.2	Q13702-1
RAPSN	ENST00000352508.7 link	c.59A>G	p.Asn20Ser	missense_variant	Exon 1 of 6	1		ENSP00000298853.3	Q13702-2
RAPSN	ENST00000529341.1 link	c.59A>G	p.Asn20Ser	missense_variant	Exon 1 of 5	1		ENSP00000431732.1	E9PK11
RAPSN	ENST00000524487.5 link	c.59A>G	p.Asn20Ser	missense_variant	Exon 1 of 7	5		ENSP00000435551.2	E9PJP9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.085

MetaRNN

Pathogenic

0.81

D;D;D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.8

L;L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Uncertain

0.54

Sift

Benign

0.043

D;D;T;D

Sift4G

Uncertain

0.028

D;D;D;D

Polyphen

0.99

D;D;.;P

Vest4

0.65

MutPred

0.66

Gain of disorder (P = 0.0399);Gain of disorder (P = 0.0399);Gain of disorder (P = 0.0399);Gain of disorder (P = 0.0399);

MVP

0.89

MPC

0.52

ClinPred

0.91

GERP RS

5.6

Varity_R

0.22

gMVP

0.066

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over