11-47449163-G-T

Variant names:

• chr11-47449163-G-T
• rs886037842
• NM_005055.5:c.-199C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005055.5(RAPSN):​c.-199C>A variant causes a upstream gene change. The variant allele was found at a frequency of 0.00000192 in 522,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: RAPSN NM_005055.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPSN	NM_005055.5	c.-199C>A		upstream_gene_variant		ENST00000298854.7	NP_005046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPSN	ENST00000298854.7	c.-199C>A		upstream_gene_variant		1	NM_005055.5	ENSP00000298854.2
RAPSN	ENST00000352508.7	c.-199C>A		upstream_gene_variant		1		ENSP00000298853.3
RAPSN	ENST00000529341.1	c.-199C>A		upstream_gene_variant		1		ENSP00000431732.1
RAPSN	ENST00000524487.5	c.-199C>A		upstream_gene_variant		5		ENSP00000435551.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000192 AC: 1 AN: 522098 Hom.: 0 Cov.: 6 AF XY: 0.00000362 AC XY: 1 AN XY: 276594

⚠️ 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: 14926

American (AMR) AF: 0.00 AC: 0 AN: 29414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16178

East Asian (EAS) AF: 0.00 AC: 0 AN: 31584

South Asian (SAS) AF: 0.0000189 AC: 1 AN: 52938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30814

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 315174

Other (OTH) AF: 0.00 AC: 0 AN: 28844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.94
PhyloP100		4.4
PromoterAI		-0.017	Neutral

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: rs886037842; hg19: chr11-47470715;