rs1425380499

Variant names:

• chr11-47438006-C-A
• rs1425380499
• NM_005055.5:c.1208G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-47438006-C-A
• chr11-47438006-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005055.5(RAPSN):​c.1208G>T​(p.Arg403Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R403H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.64
• Publications: 2 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

LOC124902673 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.1208G>T	p.Arg403Leu	missense_variant	Exon 8 of 8	ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.1208G>T	p.Arg403Leu	missense_variant	Exon 8 of 8	1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.1031G>T	p.Arg344Leu	missense_variant	Exon 6 of 6	1		ENSP00000298853.3
RAPSN	ENST00000524487.5	c.1049G>T	p.Arg350Leu	missense_variant	Exon 7 of 7	5		ENSP00000435551.2
RAPSN	ENST00000528356.1	n.163G>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000640 AC: 1 AN: 156310 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398146 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689564

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31550

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4686

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078968

Other (OTH) AF: 0.00 AC: 0 AN: 57882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.42	T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.2	M;.;.
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.033	D;D;.
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.93	P;P;.
Vest4		0.41
MutPred		0.38		Loss of MoRF binding (P = 0.0362);.;.;
MVP		0.74
MPC		0.45
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.66
Mutation Taster		=65/35	polymorphism

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: rs1425380499; hg19: chr11-47459557;