11-47437764-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_005055.5(RAPSN):c.*211G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 667,640 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (2 hom.)
• Consequence: RAPSN NM_005055.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.115

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]

LOC124902673 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152196) while in subpopulation NFE AF= 0.00401 (273/68040). AF 95% confidence interval is 0.00362. There are 0 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAPSN	NM_005055.5	c.*211G>A		3_prime_UTR_variant	8/8	ENST00000298854.7
LOC124902673	XR_007062669.1	n.141C>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAPSN	ENST00000298854.7	c.*211G>A		3_prime_UTR_variant	8/8	1	NM_005055.5	P1
RAPSN	ENST00000352508.7	c.*211G>A		3_prime_UTR_variant	6/6	1
RAPSN	ENST00000528356.1	n.405G>A		non_coding_transcript_exon_variant	2/2	3
RAPSN	ENST00000524487.5			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00252 AC: 257 AN: 101884 Hom.: 1 AF XY: 0.00236 AC XY: 129 AN XY: 54630

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000980

Gnomad ASJ exome AF: 0.00217

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000544

Gnomad FIN exome AF: 0.00431

Gnomad NFE exome AF: 0.00439

Gnomad OTH exome AF: 0.00390

GnomAD4 exome AF: 0.00315 AC: 1626 AN: 515444 Hom.: 2 Cov.: 6 AF XY: 0.00292 AC XY: 799 AN XY: 273984

Gnomad4 AFR exome AF: 0.000858

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74354

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00274

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fetal akinesia deformation sequence 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital myasthenic syndrome 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	12
Dann	Benign	0.84

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

Other links and lift over

dbSNP: rs542424704; hg19: chr11-47459315; COSMIC: COSV54085476; COSMIC: COSV54085476;