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rs193922674

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 18P and 4B. PVS1PP3_ModeratePP5_Very_StrongBS2

The NM_001005242.3(PKP2):c.2014-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000768 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000082 ( 0 hom. )

Consequence

PKP2
NM_001005242.3 splice_acceptor

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:33

Conservation

PhyloP100: 5.51
Variant links:
Genes affected
PKP2 (HGNC:9024): (plakophilin 2) This gene encodes a member of the arm-repeat (armadillo) and plakophilin gene families. Plakophilin proteins contain numerous armadillo repeats, localize to cell desmosomes and nuclei, and participate in linking cadherins to intermediate filaments in the cytoskeleton. This gene may regulate the signaling activity of beta-catenin and is required to maintain transcription of genes that control intracellular calcium cycling including ryanodine receptor 2, ankyrin-B, triadin, and calcium channel, voltage-dependent, L type, alpha 1C. Mutations in this gene are associated with different inherited cardiac conditions including Arrythmogenic Cardiomyopathy, Brugada Syndrome, and Idiopathic Ventricular Fibrillation. A processed pseudogene with high similarity to this gene has been mapped to chromosome 12p13. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 12-32802557-C-G is Pathogenic according to our data. Variant chr12-32802557-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-32802557-C-G is described in Lovd as [Pathogenic]. Variant chr12-32802557-C-G is described in Lovd as [Likely_pathogenic].
BS2
High AC in GnomAdExome at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PKP2NM_001005242.3 linkuse as main transcriptc.2014-1G>C splice_acceptor_variant ENST00000340811.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PKP2ENST00000340811.9 linkuse as main transcriptc.2014-1G>C splice_acceptor_variant 1 NM_001005242.3 P1Q99959-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251262
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135800
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000704
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000821
AC:
120
AN:
1461542
Hom.:
0
Cov.:
30
AF XY:
0.0000743
AC XY:
54
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000104
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000453
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:33
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 9 Pathogenic:20
Pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterNov 08, 2021- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 20, 2024This sequence change affects an acceptor splice site in intron 10 of the PKP2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs193922674, gnomAD 0.008%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (PMID: 15489853, 17010805, 24784157, 25087486, 27335691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6756). Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 15489853, 25087486). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteFeb 02, 2022Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with arrhythmogenic right ventricular dysplasia 9 (MIM#609040). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (ClinVar, PMID: 17010805, PMID: 23183494). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR showed skipping of exon 11, resulting in a frameshift, which is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction) (PMID: 25087486). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (9 heterozygotes, 0 homozygotes). (SP) 0701 - Other loss of function variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as pathogenic in multiple families with ARVC (ClinVar, PMID: 27335691). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria providedclinical testingZotz-Klimas Genetics Lab, MVZ Zotz KlimasNov 24, 2023- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 08, 2014- -
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterMay 31, 2017- -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJun 02, 2017This c.2146-1G>C variant has been reported in over 10 individuals with ARVD/cardiomyopathy with incomplete family segregation [PMID 15489853,17010805, 20525856, 24784157, 25087486]. This variant is located in the invariant splice acceptor site of intron 11. Functional assays showed that this change activates a cryptic splice acceptor site in intron 12 or, alternatively, another cryptic splice acceptor site in PKP2 exon 13 [PMID 15489853]. A variant affecting the same invariant splice site has also been reported in additional patients [PMID 19955750]. This variant has been detected in 6 heterozygous individuals from Europe (http://exac.broadinstitute.org/variant/12-32955491-C-G). It is thus classified as a pathogenic variant. -
Pathogenic, criteria provided, single submitterclinical testingInstitute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu MünchenDec 13, 2021- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 05, 2021- -
Pathogenic, criteria provided, single submitterresearchLaan Lab, Human Genetics Research Group, University of TartuMay 01, 2021- -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologySep 21, 2018- -
Pathogenic, criteria provided, single submitterresearchAgnes Ginges Centre for Molecular Cardiology, Centenary InstituteMar 08, 2017The PKP2 c.2146-1G>C variant has been reported in multiple ARVC probands (see literature), and has been found to segregate with disease in a few families (Dalal D et al., 2006; Groeneweg JA, et al., 2014; Svensson et al., 2016). The variant affects a canonical splice acceptor site of intron 10 and was found to result in exon 11 skipping and consequently a shift in the reading frame (Groeneweg JA, et al., 2014). The variant is present at a low frequency in the Exome Aggregation Consortium dataset (MAF= 0.00005; http://exac.broadinstitute.org/). We identified this variant in 3 male ARVC probands. 2/3 probands have no family history of disease. The other proband has family history of ARVC and sudden death, and passed away from a cardiac arrest at young age. In summary, based on LOF variants in PKP2 being an established mechanism of ARVC, multiple ARVC probands reported with the variant, cosegregation with disease and rarity in the general population, we classify PKP2 c.2146-1G>C as a "pathogenic" variant. -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterSep 28, 2023PVS1, PS4 -
Pathogenic, criteria provided, single submitterresearchHudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for BiotechnologyNov 09, 2017- -
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneMay 21, 2019- -
Pathogenic, no assertion criteria providedclinical testingInstitut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-WestfalenMay 01, 2016- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2004- -
Pathogenic, criteria provided, single submitterclinical testingGenomics England Pilot Project, Genomics England-- -
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:5
Likely pathogenic, no assertion criteria providedresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute-- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 26, 2019Variant summary: PKP2 c.2146-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing, specifically that the variant abolishes a 3' acceptor site. This prediction was confirmed by experimental evidence that demonstrated this variant affects mRNA splicing resulting in exon 11 skipping (Gerull_2004, Groeneweg_2014). The variant allele was found at a frequency of 3.2e-05 in 251262 control chromosomes (gnomAD). c.2146-1G>C has been reported in the literature in numerous individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, including unrelated families where the variant co-segregated with the disease, though incomplete co-segregation was also observed suggesting somewhat reduced penetrance (Dalal_2006, Fressart_2010, Gerull_2004, Groeneweg_2014, Syrris_2006). These data indicate that the variant is very likely to be associated with disease. Immunohistochemical studies indicated marked reduction of the PKP2 protein level in a myocardium sample from an affected individual (Asimaki_2009). 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsMay 04, 2015- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 10, 2017The c.2146-1G>C variant in PKP2 has been reported in >30 individuals with ARVC ( Gerull 2004, Syrris 2006, Dalal 2006, Wlodarska 2008, Watkins 2009, den Haan 200 9, Asimaki 2009, La Gerche 2010, Fressart 2010, Borahona-Dussault 2010, Cox 2011 , Baskin 2013, Philips 2014, Svensson 2016, Walsh 2017, LMM data, ClinVar Variat ion ID: 6756) and segregated with disease in at least 8 affected relatives from 5 families (Groeneweg 2014, Svensson 2016, LMM data). However, it has also been observed in multiple unaffected individuals over the age of 50, which suggests t hat penetrance may be reduced (Perrin 2013, Svensson 2016, LMM data). In additio n, this variant has been identified in 10/126558 European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1939 22674). Please note that for diseases with clinical variability or reduced penet rance, pathogenic variants may be present at a low frequency in the general popu lation. The c.2146-1G>C variant has been shown to cause skipping of exon 11, res ulting in a frameshift (p.Pro716fs) and premature termination 32 amino acids dow nstream, ultimately leading to a marked reduction of PKP2 protein in the myocard ium (Gerull 2004, Asimaki 2009, Groeneweg 2014). Heterozygous loss of PKP2 funct ion is an established disease mechanism in individuals with ARVC. In summary, th is variant meets criteria to be classified as pathogenic for ARVC in an autosoma l dominant manner; however, it should be noted that penetrance may be reduced. A CMG/AMP Criteria applied: PVS1, PS4, PM2, PP1_Moderate (Richards 2015). -
not provided Pathogenic:4
Pathogenic, no assertion criteria providedclinical testingStanford Center for Inherited Cardiovascular Disease, Stanford UniversityJun 20, 2014Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS10-1 G>C (c.2146-1 G>C) in intron 10 of the PKP2 gene (NM_004572.3) Given the strong case data and the fact that many splicing variants in PKP2 have been implicated in ARVC, we consider this variant very likely disease causing. The variant has been seen in at least 37 unrelated cases of ARVC (not including this patient's family). There is weak segregation data. Gerull et al (2004) observed the variant in two of 120 unrelated patients with ARVC of European decent who underwent sequencing of PKP2. Syrris et al (2006) observed the variant in one of 100 white patients from their British ARVC cohort (McKenna's group). Dalal et al (2006) observed the variant in 7 of 58 patients with ARVC in the Hopkins ARVC registry (note that 15 patients in the cohort were also enrolled in the national ARVC registry so may overlap with other reports). The same group reported in a separate paper on two of these families; in one family two affected invidiuals had the variant while in the other family two identical twins both had the variant. This group later reported on analysis of PKP2, DSG2, DSP, DSC2, and JUP in 82 patients with ARVC from the Hopkins registry; 10 patients have this variant, which appears to include the 7 previously reported (den Haan et al 2009). One of these patients had two additional desmosomal variant including a PKP2 missense previously reported with ARVC and a DSG2 missense that has been seen more frequently in both left and right sided cardiomyopathy than in controls and is hypothesized to be a modifier. The Hopkins cases appear to be included in several subsequent publications by their group (Tan et al 2010, Xu et al 2010). Wlodarska et al (2008) in an ESC abstract reported that they observed the variant in one of 42 patients with ARVC who underwent PKP2 screening by DHLPC and sequencing. Ancestry is not noted. Authors are from Italy and Poland. Watkins et al (2009) reported the variant in 1 of 50 unrelated ARVC paitents from their South African registry. Ancestry is not noted. Asimaki et al (2009) include an ARVC patient with this variant in their study on immunhistochemistry findings in ARVC. Unfortunately it is not noted how this patient was ascertained. Given this list of co-authors I suspect the case may come from the Hopkins cohort and thus overlaps with their reports (den Haan et al 2009, Dalal et al 2008). La Gerche et al (2010) analysed desmosomal genes in 47 endurance athletes with complex ventricular arrhythmias with right ventricular morphology. They observed this variant in two of those cases. Unfortunately individual phenotypic data is not provided. Two-thirds of athletes with a pathogenic variant met task force criteria for an ARVC diagnosis. Fressart et al (2010) sequenced five desmosomal genes in 135 patients with ARVC from their French and Swiss cohort and observed the variant in 7 unrelated patients. Borahona-Dussaul et al (2010) observed the variant in one of 23 patients with ARVC from their cohort in Montreal. Cox et al (2011) analyzed five desmosomal genes in their Dutch cohort of 149 ARVC patients and observed this variant in 7 patients. Baskin et al (2013) reported on sequencing of ARVC genes in 195 patients with suspected ARVC either seen in their clinic in Toronto or referred for genetic testing at their Toronto laboratory. Five patients had this variant. Perrin et al (2013) include a patient with this variant in their study on exercise testing in asymptomatic carriers; given the author list this patient was likely drawn from one of the previously published families. Nested RT-PCR on an ARVC patient with this variant showed an aberrant splicing product consistent with altered splicing (Ge -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023PKP2: PVS1, PS4:Moderate -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 29, 2022Reported in multiple individuals with ARVC referred for testing at GeneDx and in published literature (Gerull et al., 2004; Syrris et al., 2006; Dalal et al., 2006; den Haan et al., 2009; Watkins et al., 2009; Fressart et al., 2010; Tan et al., 2010; Perrin et al., 2013; Kant et al., 2016; Svensson et al., 2016); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional studies revealed c.2146-1 G>C causes skipping of exon 11, resulting in a shift in reading frame (Groeneweg et al., 2014); This variant is associated with the following publications: (PMID: 20525856, 20152563, 16415378, 19279339, 30790397, 30868567, 21606390, 20864495, 25525159, 19880068, 20857253, 15489853, 17010805, 18554203, 20031617, 20400443, 27335691, 26676851, 24784157, 23810883, 28518168, 28253841, 29997227, 27532257, 24585727, 23812740, 21636032, 21606396, 28177452, 26264440, 25351510, 19863551, 19302745, 29253866, 30998997, 30677492, 19955750, 16549640, 31737537, 31447099, 25825460, 32372669, 31386562, 31402444, 25087486, 32522011, 33232181, 33238575, 32686758, 34135346, 33087929) -
Cardiomyopathy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthFeb 27, 2023This variant causes a G to C nucleotide substitution at the -1 position of intron 10 splice acceptor site of the PKP2 gene. Functional RNA studies have shown that this variant causes skipping of exon 11 and a premature truncation of the PKP2 gene product (PMID: 15489853, 25087486). This variant has been reported in over 40 individuals affected with arrhythmogenic cardiomyopathy (PMID: 15489853, 17010805, 17010805, 20031617, 20400443, 20857253, 23178689, 24784157, 25087486, 25087486, 27335691, 28523642, 35579515) and has been shown to segregate with disease in multiple families (PMID: 25087486, 27335691). This variant has been identified in 9/282670 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of PKP2 function is a known mechanism of disease (clinicalgenome.org). Based on available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioMar 10, 2022- -
PKP2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 25, 2024The PKP2 c.2146-1G>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant is also referred to as c.2014-1G>C using an alternate transcript (NM_001005242.3). This variant has been reported to be causative for arrhythmogenic right ventricular dysplasia (ARVD; Gerull et al. 2004. PubMed ID: 15489853; La Gerche et al. 2010. PubMed ID: 20525856; Perrin et al. 2013. PubMed ID: 23810883; OMIM #609040). In ClinVar, this variant is interpreted as pathogenic by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/6756/). Furthermore, protein truncating variants up and downstream of this variant have been reported to be causative for ARVD (Gerull et al. 2004. PubMed ID: 15489853; Bao et al. 2013. PubMed ID: 24125834; Walsh et al. 2017. PubMed ID: 27532257). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 08, 2022The c.2146-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 11 of the PKP2 gene. This mutation has been observed in numerous unrelated individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) and was shown to segregate with disease in multiple families, though penetrance and expressivity were variable (Gerull B et al. Nat. Genet. 2004;36(11):1162-4; Dalal D et al. J. Am. Coll. Cardiol. 2006;48(7):1416-24, Svensson A et al Am. J. Cardiovasc. Dis. 2016;6(2):55-65). Functional studies on mRNA demonstrated that this mutation results in exon 11 skipping (Groeneweg JA et al. Heart Rhythm 2014;11(11):2010-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.34
Cadd
Pathogenic
28
Dann
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.93
D
MutationTaster
Benign
1.0
A;A
GERP RS
4.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.98
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922674; hg19: chr12-32955491; API