11-47447869-G-C

Variant names:

• chr11-47447869-G-C
• rs56245238
• NM_005055.5:c.474C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_005055.5(RAPSN):​c.474C>G​(p.Asp158Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D158G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• Publications: 0 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), PanelApp Australia, 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_005055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.474C>G	p.Asp158Glu	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.474C>G	p.Asp158Glu	missense_variant	Exon 2 of 8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.474C>G	p.Asp158Glu	missense_variant	Exon 2 of 6	1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.474C>G	p.Asp158Glu	missense_variant	Exon 2 of 5	1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.474C>G	p.Asp158Glu	missense_variant	Exon 2 of 7	5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	7.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.4	M;M;.;.
PhyloP100		0.82
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;D
Polyphen		0.86	P;D;.;D
Vest4		0.57
MutPred		0.70		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.88
MPC		0.61
ClinPred		0.99	D
GERP RS		-2.9
Varity_R		0.69
gMVP		0.46
Mutation Taster		=47/53	disease causing

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: rs56245238; hg19: chr11-47469421;