chr11-47448102-A-G

Variant names:

• chr11-47448102-A-G
• rs57878668
• NM_005055.5:c.241T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005055.5(RAPSN):​c.241T>C​(p.Phe81Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00569 in 1,613,790 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (47 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (84 hom.)
• Consequence: RAPSN NM_005055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.92
• 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: Labcorp Genetics (formerly Invitae), G2P
• neuromuscular disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• congenital myasthenic syndrome 11

  Inheritance: AR Classification: STRONG Submitted by: 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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005055.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.006080568).
• BP6: Variant 11-47448102-A-G is Benign according to our data. Variant chr11-47448102-A-G is described in ClinVar as Benign. ClinVar VariationId is 235304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0173 (2625/152168) while in subpopulation AFR AF = 0.0481 (1996/41500). AF 95% confidence interval is 0.0463. There are 47 homozygotes in GnomAd4. There are 1290 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 47 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.241T>C	p.Phe81Leu	missense	Exon 2 of 8	NP_005046.2
	RAPSN	NM_001440490.1		c.241T>C	p.Phe81Leu	missense	Exon 2 of 8	NP_001427419.1
	RAPSN	NM_001440491.1		c.241T>C	p.Phe81Leu	missense	Exon 2 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.241T>C	p.Phe81Leu	missense	Exon 2 of 8	ENSP00000298854.2	Q13702-1
	RAPSN	ENST00000352508.7	TSL:1	c.241T>C	p.Phe81Leu	missense	Exon 2 of 6	ENSP00000298853.3	Q13702-2
	RAPSN	ENST00000529341.1	TSL:1	c.241T>C	p.Phe81Leu	missense	Exon 2 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2621 AN: 152050 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00786 AC: 1969 AN: 250414 AF XY: 0.00686

Gnomad AFR exome AF: 0.0499

Gnomad AMR exome AF: 0.00382

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0133

Gnomad NFE exome AF: 0.00575

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.00448 AC: 6552 AN: 1461622 Hom.: 84 Cov.: 36 AF XY: 0.00437 AC XY: 3179 AN XY: 727126

African (AFR) AF: 0.0491 AC: 1645 AN: 33480

American (AMR) AF: 0.00396 AC: 177 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86258

European-Finnish (FIN) AF: 0.0128 AC: 683 AN: 53168

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.00311 AC: 3456 AN: 1111996

Other (OTH) AF: 0.00651 AC: 393 AN: 60396

GnomAD4 genome AF: 0.0173 AC: 2625 AN: 152168 Hom.: 47 Cov.: 32 AF XY: 0.0173 AC XY: 1290 AN XY: 74390

African (AFR) AF: 0.0481 AC: 1996 AN: 41500

American (AMR) AF: 0.00510 AC: 78 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00518 AC: 352 AN: 67984

Other (OTH) AF: 0.0104 AC: 22 AN: 2106

Alfa AF: 0.00770 Hom.: 39

Bravo AF: 0.0173

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0518 AC: 228

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00912 AC: 1107

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.015
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		6.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.072
Sift	Benign	0.48	T
Sift4G	Benign	0.51	T
Polyphen		0.0030	B
Vest4		0.24
MutPred		0.14		Loss of helix (P = 0.1299)
MVP		0.78
MPC		0.18
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.16
gMVP		0.37
Mutation Taster		=99/1	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: rs57878668; hg19: chr11-47469654;