Genetic Variant RAPSN:p.Pro381Pro (chr11-47438755-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005055.5(RAPSN):c.1143T>C(p.Pro381Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,562,730 control chromosomes in the GnomAD database, including 382,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 31106 hom., cov: 32)

Exomes 𝑓: 0.70 ( 351469 hom. )

Consequence

RAPSN
NM_005055.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.206

Publications

41 publications found

Variant links:

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

RAPSN links:

LOC124902673 (HGNC:):

LOC124902673 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 11-47438755-A-G is Benign according to our data. Variant chr11-47438755-A-G is described in ClinVar as Benign. ClinVar VariationId is 130089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.206 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RAPSN	NM_005055.5	MANE Select	c.1143T>C	p.Pro381Pro	synonymous	Exon 7 of 8	NP_005046.2
RAPSN	NM_001440490.1		c.1279T>C	p.Leu427Leu	synonymous	Exon 7 of 8	NP_001427419.1
RAPSN	NM_001440491.1		c.1228T>C	p.Leu410Leu	synonymous	Exon 7 of 8	NP_001427420.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAPSN	ENST00000298854.7	TSL:1 MANE Select	c.1143T>C	p.Pro381Pro	synonymous	Exon 7 of 8	ENSP00000298854.2	Q13702-1
RAPSN	ENST00000352508.7	TSL:1	c.966T>C	p.Pro322Pro	synonymous	Exon 5 of 6	ENSP00000298853.3	Q13702-2
RAPSN	ENST00000529341.1	TSL:1	c.966T>C	p.Pro322Pro	synonymous	Exon 5 of 5	ENSP00000431732.1	E9PK11

Frequencies

GnomAD3 genomes

AF:

0.625

AC:

94917

AN:

151888

Hom.:

31092

Cov.:

show subpopulations

Gnomad AFR

AF:

0.418

Gnomad AMI

AF:

0.868

Gnomad AMR

AF:

0.668

Gnomad ASJ

AF:

0.716

Gnomad EAS

AF:

0.659

Gnomad SAS

AF:

0.784

Gnomad FIN

AF:

0.607

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.720

Gnomad OTH

AF:

0.684

GnomAD2 exomes

AF:

0.664

AC:

121435

AN:

182762

AF XY:

0.678

show subpopulations

Gnomad AFR exome

AF:

0.396

Gnomad AMR exome

AF:

0.606

Gnomad ASJ exome

AF:

0.719

Gnomad EAS exome

AF:

0.623

Gnomad FIN exome

AF:

0.611

Gnomad NFE exome

AF:

0.704

Gnomad OTH exome

AF:

0.720

GnomAD4 exome

AF:

0.703

AC:

991432

AN:

1410724

Hom.:

351469

Cov.:

AF XY:

0.706

AC XY:

491249

AN XY:

695834

show subpopulations

African (AFR)

AF:

0.407

AC:

13329

AN:

32744

American (AMR)

AF:

0.619

AC:

24021

AN:

38776

Ashkenazi Jewish (ASJ)

AF:

0.720

AC:

17958

AN:

24958

East Asian (EAS)

AF:

0.593

AC:

22263

AN:

37520

South Asian (SAS)

AF:

0.768

AC:

61420

AN:

80026

European-Finnish (FIN)

AF:

0.623

AC:

31169

AN:

50028

Middle Eastern (MID)

AF:

0.742

AC:

4223

AN:

5688

European-Non Finnish (NFE)

AF:

0.717

AC:

775845

AN:

1082732

Other (OTH)

AF:

0.707

AC:

41204

AN:

58252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

16926

33852

50778

67704

84630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19564

39128

58692

78256

97820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.625

AC:

94972

AN:

152006

Hom.:

31106

Cov.:

AF XY:

0.623

AC XY:

46278

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.418

AC:

17307

AN:

41450

American (AMR)

AF:

0.669

AC:

10214

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.716

AC:

2486

AN:

3470

East Asian (EAS)

AF:

0.658

AC:

3392

AN:

5152

South Asian (SAS)

AF:

0.783

AC:

3774

AN:

4822

European-Finnish (FIN)

AF:

0.607

AC:

6410

AN:

10568

Middle Eastern (MID)

AF:

0.721

AC:

212

AN:

294

European-Non Finnish (NFE)

AF:

0.720

AC:

48932

AN:

67962

Other (OTH)

AF:

0.688

AC:

1453

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1753

3506

5258

7011

8764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

772

1544

2316

3088

3860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.701

Hom.:

69504

Bravo

AF:

0.617

Asia WGS

AF:

0.720

AC:

2508

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Congenital myasthenic syndrome 11 (2)

Congenital myasthenic syndrome (1)

Fetal akinesia deformation sequence 1 (1)

Fetal akinesia deformation sequence 1;C4225367:Congenital myasthenic syndrome 11 (1)

Fetal akinesia deformation sequence 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.6

(source)

DANN

Benign

0.77

PhyloP100

0.21

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over