rs104894299

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-47448079-G-C
• chr11-47448079-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1 PM2 PP3_Strong PP5

The NM_005055.5(RAPSN):​c.264C>G​(p.Asn88Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: Transcript NM_005055.5 (RAPSN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 11-47448079-G-C is Pathogenic according to our data. Variant chr11-47448079-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3359227.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.264C>G	p.Asn88Lys	missense_variant	Exon 2 of 8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.264C>G	p.Asn88Lys	missense_variant	Exon 2 of 8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.264C>G	p.Asn88Lys	missense_variant	Exon 2 of 6	1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.264C>G	p.Asn88Lys	missense_variant	Exon 2 of 5	1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.264C>G	p.Asn88Lys	missense_variant	Exon 2 of 7	5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 11 Pathogenic:1

Oct 19, 2023

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.048	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;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.0030	D
MutationAssessor	Benign	0.97	L;L;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.96
MutPred		0.88		Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);Gain of ubiquitination at N88 (P = 0.0452);
MVP		0.89
MPC		0.70
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.85
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-47469631;