11-47442732-C-T

Variant names:

• chr11-47442732-C-T
• rs34625105
• NM_005055.5:c.614G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005055.5(RAPSN):​c.614G>A​(p.Arg205Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0152 in 1,614,256 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R205W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.016 (237 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.19
• Publications: 7 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077343583).
• BP6: Variant 11-47442732-C-T is Benign according to our data. Variant chr11-47442732-C-T is described in ClinVar as Benign. ClinVar VariationId is 259630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0114 (1735/152366) while in subpopulation AMR AF = 0.0199 (305/15302). AF 95% confidence interval is 0.0181. There are 28 homozygotes in GnomAd4. There are 811 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005055.5. 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.614G>A	p.Arg205Gln	missense	Exon 3 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.614G>A	p.Arg205Gln	missense	Exon 3 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.614G>A	p.Arg205Gln	missense	Exon 3 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.614G>A	p.Arg205Gln	missense	Exon 3 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.614G>A	p.Arg205Gln	missense	Exon 3 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.614G>A	p.Arg205Gln	missense	Exon 3 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1730 AN: 152248 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00971

Gnomad FIN AF: 0.00715

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.0162 AC: 4069 AN: 251422 AF XY: 0.0148

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00739

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0156 AC: 22752 AN: 1461890 Hom.: 237 Cov.: 34 AF XY: 0.0150 AC XY: 10880 AN XY: 727246

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.0455 AC: 2036 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00421 AC: 110 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.00881 AC: 760 AN: 86258

European-Finnish (FIN) AF: 0.00771 AC: 412 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18495 AN: 1112008

Other (OTH) AF: 0.0137 AC: 827 AN: 60396

GnomAD4 genome AF: 0.0114 AC: 1735 AN: 152366 Hom.: 28 Cov.: 33 AF XY: 0.0109 AC XY: 811 AN XY: 74506

African (AFR) AF: 0.00274 AC: 114 AN: 41592

American (AMR) AF: 0.0199 AC: 305 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00972 AC: 47 AN: 4834

European-Finnish (FIN) AF: 0.00715 AC: 76 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1082 AN: 68036

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0138 Hom.: 60

Bravo AF: 0.0121

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0152 AC: 1844

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0129

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome (1)
-	-	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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0077	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.17
Sift	Benign	0.032	D
Sift4G	Uncertain	0.051	T
Polyphen		0.74	P
Vest4		0.74
MPC		0.26
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.34
gMVP		0.56
Mutation Taster		=45/55	polymorphism (auto)

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: rs34625105; hg19: chr11-47464284;