rs72905825

Variant names:

• chr11-47448803-C-T
• rs72905825
• NM_005055.5:c.162G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001440490.1(RAPSN):​c.162G>A​(p.Ser54Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,612,718 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (24 hom.)
• Consequence: RAPSN NM_001440490.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -2.70
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 11-47448803-C-T is Benign according to our data. Variant chr11-47448803-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259625.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00333 (507/152354) while in subpopulation NFE AF = 0.00513 (349/68030). AF 95% confidence interval is 0.00469. There are 0 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440490.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPSN	NM_005055.5	MANE Select	c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 8	NP_001427420.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 8	ENSP00000298854.2
	RAPSN	ENST00000352508.7	TSL:1	c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 6	ENSP00000298853.3
	RAPSN	ENST00000529341.1	TSL:1	c.162G>A	p.Ser54Ser	synonymous	Exon 1 of 5	ENSP00000431732.1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00341 AC: 852 AN: 250136 AF XY: 0.00333

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00577

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00431

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00434 AC: 6344 AN: 1460364 Hom.: 24 Cov.: 32 AF XY: 0.00421 AC XY: 3059 AN XY: 726586

African (AFR) AF: 0.000866 AC: 29 AN: 33478

American (AMR) AF: 0.00402 AC: 180 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00582 AC: 152 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.00362 AC: 188 AN: 51934

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00486 AC: 5402 AN: 1111986

Other (OTH) AF: 0.00566 AC: 342 AN: 60388

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.00342 AC XY: 255 AN XY: 74500

African (AFR) AF: 0.000769 AC: 32 AN: 41592

American (AMR) AF: 0.00340 AC: 52 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68030

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00485 Hom.: 0

Bravo AF: 0.00357

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00456

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	1	-	Congenital myasthenic syndrome 11 (1)
-	-	1	Fetal akinesia deformation sequence 1 (1)
-	-	1	Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	5.2
DANN	Benign	0.88
PhyloP100		-2.7
PromoterAI		-0.038	Neutral
Mutation Taster		=98/2	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: rs72905825; hg19: chr11-47470355; COSMIC: COSV100100470;