rs199473603

Variant names:

• chr3-38562467-G-A
• rs199473603
• NM_001099404.2:c.3911C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-38562467-G-A
• chr3-38562467-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PP3_Strong

The NM_001099404.2(SCN5A):​c.3911C>T​(p.Thr1304Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000343 in 1,613,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/24 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1304T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:16 B:1 O:1
• Conservation: PhyloP100: 10.0
• Publications: 45 publications found

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_001099404.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3911C>T	p.Thr1304Met	missense_variant	Exon 22 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3908C>T	p.Thr1303Met	missense_variant	Exon 22 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3911C>T	p.Thr1304Met	missense_variant	Exon 22 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3908C>T	p.Thr1303Met	missense_variant	Exon 22 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000178 AC: 44 AN: 247644 AF XY: 0.000208

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000357 AC: 521 AN: 1461146 Hom.: 0 Cov.: 31 AF XY: 0.000341 AC XY: 248 AN XY: 726770

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.0000896 AC: 4 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000814 AC: 7 AN: 86042

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53368

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.000429 AC: 477 AN: 1111688

Other (OTH) AF: 0.000414 AC: 25 AN: 60348

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74480

African (AFR) AF: 0.0000722 AC: 3 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000392 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.000207 AC: 25

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:16 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1304 of the SCN5A protein (p.Thr1304Met). This variant is present in population databases (rs199473603, gnomAD 0.03%). This missense change has been observed in individual(s) with SCN5A-related conditions (PMID: 10508990, 17210839, 17210841, 19716085, 19841300, 24631775, 25210526, 28341588, 30847666). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67835). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN5A function (PMID: 17210841). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nov 16, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with various cardiac phenotypes, including LQTS, Brugada syndrome, lone atrial fibrillation, sudden infant death syndrome, cardiomyopathy, and T-wave inversion (PMID: 17210839, 10508990, 10973849, 19716085, 22685113, 25210526, 23465283, 29764897, 31514951, 34065239); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have been reported and show conflicting results (PMID: 17210841, 24613995); This variant is associated with the following publications: (PMID: 10973849, 19716085, 28316956, 31514951, 30193851, 22685113, 23465283, 22378279, 25637381, 25210526, 10961955, 18503232, 23272275, 24055113, 24613995, 25351510, 25410959, 25904541, 25898860, 27153395, 29247119, 28412158, 28341588, 30677491, 28988457, 31019283, 31043699, 32048431, 30291343, 30847666, 29764897, 26743238, 19841300, 24144883, 24631775, 26746457, 31395126, 34426522, 34065239, 34621001, 34461752, 33772059, 35060774, 30203441, 10508990, 17210839, 29790872, 17210841, 37937776, 36396199, 35534676, 36129056, 37965733) -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SCN5A: PP3 -

Mar 31, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Feb 18, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.3911C>T; p.Thr1304Met variant (rs199473603) is reported in the literature in individuals affected with long QT syndrome (Kapa 2009, Wattanasirichaigoon 1999) or Brugada syndrome (Kim 2014), which have different mechanisms of pathogenicity. This variant is also reported with conflicting interpretations by multiple laboratories in ClinVar (Variation ID: 67835), and is found in the non-Finnish European population with an allele frequency of 0.031% (40/127748 alleles) in the Genome Aggregation Database. The threonine at codon 1304 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, functional analyses of the variant protein show conflicting effects on channel function (Beyder 2014, Wang 2007). Due to conflicting information, the clinical significance of the p.Thr1304Met variant is uncertain at this time. References: Beyder A et al. Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome. Gastroenterology. 2014 Jun;146(7):1659-1668. Kapa S et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Kim G et al. A pediatric case of Brugada syndrome diagnosed by fever-provoked ventricular tachycardia. Korean J Pediatr. 2014 Aug;57(8):374-8. Wang DW et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation. 2007 Jan 23;115(3):368-76. Wattanasirichaigoon D et al. Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations. Am J Med Genet. 1999 Oct 29;86(5):470-6. -

Brugada syndrome 1 Uncertain:4

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Medical Genetics Clinic, University of Catania

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SCN5A c.3911C>T variant (rs199473603) is present in population databases (gnomAD 0.03%). Computational prediction analyses (Polyphen-2, SIFT) suggest that this variant has deleterious effect on protein structure and function. Functional studies have shown conflicting results in channel function (PMID: 17210841, 24613995). This variant was reported in individuals with long QT syndrome (PMID: 17210839, 19716085, 19841300); Brugada syndrome (PMID: 34461752, 25210526), sudden unexplained death (PMID: 17210839, 17210841, 24631775, 32652122). Based on conflicting evidence, the clinical role of SCN5A c.3911C>T variant cannot be determined. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 20, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Long QT syndrome 3 Pathogenic:2 Uncertain:1

Jan 04, 2024

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Sep 13, 2013

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant has been previously reported as disease-causing. It was an incidental finding in our study, maternally inherited in a 8-year-old male with medulloblastoma. -

not specified Uncertain:2

Apr 29, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.3911C>T (p.Thr1304Met) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 247644 control chromosomes. The observed variant frequency is approximately 8.53 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Long QT Syndrome phenotype (2.1e-05). c.3911C>T has been reported in the literature in individuals affected with Long QT Syndrome and other related conditions (e.g. Wattanasirichaigoon_1999, Arnestad_2007, Kapplinger_2009, Kapa_2009, van Lint_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrates an affect on protein function (Wang_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17210839, 37937776, 35534676, 19841300, 19716085, 36396199, 17210841, 10508990, 39486665, 36129056, 30847666). ClinVar contains an entry for this variant (Variation ID: 67835). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Apr 26, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr1304Met variant in SCN5A has been reported in 3 individuals with long Q T syndrome, 1 infant with sudden infant death syndrome, 1 individual with Brugad a syndrome, 1 individual with early-onset atrial fibrillation (Wattanasirichaigo on 1999, Priori 2000, Splawski 2000, Arnestad 2007, Olesen 2012, Kim 2014). This variant segregated with LQTS in 2 affected relatives from 1 family and with Br ugada syndrome in 1 affected relative from 1 family. However, other clinical lab oratories have observed this variant in individuals who carried other disease-ca using variants (GeneDx, Emory, Invitae; personal communication) and this variant has been reported in multiple healthy individuals (Weeke 2015, Kapplinger 2015) . Additionally, it is unclear if the same variant would be causative for such a diverse set of phenotypes, suggesting that it may not have a functional effect. This variant has also been identified in 0.03% (35/126116) of European chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199473603). Additionally, in vitro functional studies have shown confli cting results (Want 2007, Makita 2008, Beyder 2014). In summary, due to the pres ence of conflicting data, the clinical significance of the p.Thr1304Met variant is uncertain. ACMG/AMP Criteria applied: PP1; BP5. -

Brugada syndrome Pathogenic:1

Jan 13, 2017

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Long QT syndrome Pathogenic:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

SCN5A-related disorder Uncertain:1

Apr 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SCN5A c.3911C>T variant is predicted to result in the amino acid substitution p.Thr1304Met. This variant was reported in individuals with long QT syndrome and Brugada syndrome (Wattanasirichaigoon et al. 1999. PMID: 10508990; Arnestad et al. 2007. PMID: 17210839; Kapplinger et al. 2009. PMID: 19716085; Kapa et al. 2009. PMID: 19841300; Table SVI, Milman et al. 2021. PubMed ID: 34461752). Functional studies showed conflicting evidences of pathogenicity for this variant. Although one study suggested this variant significantly increased persistent sodium currents and faster recovery from inactivation (Wang et al. 2007. PMID: 17210841), another demonstrated no difference from wild type SCN5A (Beyder et al. 2014. PubMed ID: 24613995). This variant also had conflicting interpretations of pathogenicity in the literature ranging from benign to pathogenic (Table S1, Amendola et al. 2015. PMID: 25637381; Table S1, Paludan-Müller et al. 2019. PubMed ID: 31043699; Table SVI, Milman et al. 2021. PubMed ID: 34461752). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, uncertain significance, likely pathogenic, and pathogenic in ClinVar (www.ncbi.nlm.nih.gov/clinvar/variation/67835/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Conduction disorder of the heart Uncertain:1

Jan 17, 2020

Robert's Program, Boston Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

This variant is classified as a Variant of Uncertain Significance based on the following ACMG/AMP criteria: BS2, PP3, and PS3. Published functional in vitro and in vivio evidence (Wang et al 2007, Anderson et al 2017) supports this variant having an effect on the SCN5A protein, but population frequency (MAF of 0.0003 in non-finnish Europeans) is high compared to frequency of disease. -

Cardiovascular phenotype Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T1304M variant (also known as c.3911C>T), located in coding exon 21 of the SCN5A gene, results from a C to T substitution at nucleotide position 3911. The threonine at codon 1304 is replaced by methionine, an amino acid with similar properties, and is located in the transmembrane DIII-S4 region. This alteration has been reported in association with long QT syndrome (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). In one family, alteration carriers showed variable clinical and electrophysiological phenotypes with several having borderline findings (Wattanasirichaigoon D et al. Am. J. Med. Genet., 1999 Oct;86:470-6). This alteration was also detected in individuals with a transient Brugada pattern, lone atrial fibrillation, or sudden infant death syndrome (Wang DW et al. Circulation, 2007 Jan;115:368-76; Olesen MS et al. Circ Cardiovasc Genet, 2012 Aug;5:450-9; Wang D et al. Forensic Sci. Int., 2014 Apr;237:90-9; Kim G et al. Korean J Pediatr, 2014 Aug;57:374-8). In addition, this alteration was reported in hypertrophic cardiomyopathy, dilated cardiomyopathy cohorts as well as exome sequencing and cohorts not selected for the presence of cardiovascular disease; however, limited clinical information was provided (Andreasen C et al. Can J Cardio. 2013;29(9):1104-9; Dorschner MO et al. Am J Hum Genet. 2013;93(4):631-40; Lopes LR et al. Heart, 2015 Feb;101:294-301; Amendola LM et al. Genome Res., 2015 Mar;25:305-15; Van Driest SL et al. JAMA, 2016 Jan;315:47-57; Gigli M et al. J Am Coll Cardiol. 2019 09;74(11):1480-1490; Diebold I et al. Hum Mutat. 2020 05;41(5):1025-1032). While some research groups reported that this alteration would lead to gain of function effects (Wang DW et al. Circulation, 2007 Jan;115:368-76; Arnestad M et al. Circulation, 2007 Jan;115:361-7), others found no significant difference between mutant and wild type channel function (Beyder A et al. Gastroenterology, 2014 Jun;146:1659-1668; Makita N et al. J. Clin. Invest., 2008 Jun;118:2219-29); however, the experimental systems were not the same and the physiological significance of these results is unclear. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia Benign:1

Feb 18, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital long QT syndrome Other:1

-

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10508990;PMID:10961955;PMID:17210839;PMID:19716085;PMID:19841300;PMID:17210841;PMID:22378279;PMID:22685113). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
CardioboostArm	Pathogenic	1.0
CardioboostCm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;.;.;.;.;H;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;D;D;.;.
Vest4		0.95
MVP		0.99
MPC		1.5
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.83
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs199473603; hg19: chr3-38603958; COSMIC: COSV61127198;