19-11100236-C-G

Position:

• chr19-11100236-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PS4 PM2 PS3_Moderate PP3 PP4 PP1

This summary comes from the ClinGen Evidence Repository: NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows:PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed.PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1).PS3_moderate: PMID:1301956 - Level 2 assay- study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%.PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible- 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6- 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6- 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6-as well as >10 cases from (PMID:1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology)PP3: REVEL = 0.759PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. LINK:https://erepo.genome.network/evrepo/ui/classification/CA041664/MONDO:0007750/013

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (1 hom.)
• Consequence: LDLR ENST00000558518.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:30 B:1
• Conservation: PhyloP100: -0.152

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLR	NM_000527.5	c.81C>G	p.Cys27Trp	missense_variant	2/18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.81C>G	p.Cys27Trp	missense_variant	2/18	1	NM_000527.5	ENSP00000454071	P3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151930 Hom.: 0 Cov.: 32

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250746 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135548

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1460888 Hom.: 1 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 726738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74178

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000296 Hom.: 2197

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:30 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hypercholesterolemia, familial, 1 Pathogenic:20 Benign:1

Pathogenic, reviewed by expert panel	curation	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	May 06, 2022	NM_000527.5(LDLR):c.81C>G (p.Cys27Trp) variant is classified as pathogenic for Familial Hypercholesterolemia by applying evidence code PM1, PM2, PS3_moderate, PS4, PP1, PP3 and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM1: Variant meets PM2 and alters Cys27, one of the cysteine residues listed. PM2: PopMax MAF = 0.00003518 (0.004%) in European (non-Finnish) exomes (gnomAD v2.1.1). PS3_moderate: PMID:1301956 - Level 2 assay - study on hmz patient's fibroblast cell, LDLR activity value range: 15-30%. PS4: Variant meets PM2. Variant identified in >15 index cases - 1 case from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation) with Simon Broome possible - 1 case from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) with Dutch lipid clinic network >=6 - 2 cases from Robarts Research Institute with Dutch lipid clinic network >=6 - 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca with Dutch lipid clinic network >=6 -as well as >10 cases from (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425) PP1: Variant segregates with FH phenotype in at least 2 informative meiosis (minimum 2) from 2 families from different labs (Research Lab of Molecular Genetics of Lipid Metabolism - Prof. M.Arca, and Laboratory of Genetics and Molecular Cardiology) PP3: REVEL = 0.759 PP4: Variant meets PM2 and is identified in several index case who fulfil SB/DLCN>6/MedPed/other criteria for FH from different labs (see PS4), after alternative causes of high cholesterol were excluded. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 16, 2024	This missense variant replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant is also known as p.Cys6Trp in the mature protein, and as FH San Francisco in the literature. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. A functional study using cells derived from a homozygous carrier individual has shown that this variant causes the mutant protein to retain 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been reported in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352, 37370883). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in three individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.79_81delinsCGT (p.Cys27Arg), is considered to be disease-causing (ClinVar variation ID: 921285), suggesting that cysteine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	LDLR-LOVD, British Heart Foundation	Mar 25, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 26, 2024	Criteria applied: PS4,PM2,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jul 20, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	Jan 21, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	Mar 30, 2017	ACMG Guidelines: Pathogenic (ii) -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Cys27Trp variant in LDLR has been reported in 54 individuals (including 47 Greek individuals) with Familial Hypercholesterolemia (PMID: 11317361, 11668627, 9259195, 1301956, 25463123, 19026292), segregated with disease in 37 affected relatives from 18 families, and has been identified in 0.003518% (4/113686) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs2228671). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic, likely pathogenic, and likely benign in ClinVar (Variation ID: 226304). In vitro functional studies provide some evidence that the p.Cys27Trp variant may slightly impact protein function (PMID: 1301956). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with Familial Hypercholesterolemia and greater prevalence in individuals with Familial Hypercholesterolemia than in control cohorts. ACMG/AMP Criteria applied: PS4, PP1_Strong, PP3, PS3_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Robarts Research Institute, Western University	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	Apr 16, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Aug 06, 2018	The mutation at the protein level at position 27 (position 6 of the mature protein) leads to the amino acid change of cysteine to tryptophan (p.Cys27Trp, old nomenclature: p.Cys6Trp). This change has already been described in the literature as a San Francisco allele and is associated with elevated cholesterol and LDL-C levels. Impairment of LDL receptor activity has been demonstrated. We observed a patient with that kind of mutation with average values of TC = 330 and LDL-C of 280 mg/dl. PMID: 1301956, 23375686, 27497240 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jun 13, 2024	PM1, PM2, PM5, PP3, PP5- This variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 226304). Low frequency in gnomAD population databases. -
Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Damaging -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	Nov 05, 2016	Disrupt disulfide bridge between Cys27 and Cys39. -
Pathogenic, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	May 24, 2021	- -
Likely pathogenic, criteria provided, single submitter	research	Fundacion Hipercolesterolemia Familiar	Mar 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 14, 2022	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2020	Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jan 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	LDLR: PM1, PM2, PP4:Moderate, PS4:Moderate, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2021	Also known as p.(C6W) or FH San Francisco; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Participates in disulfide bonding with another cysteine residue which is critical for correct protein structure, and is located in the LDL-receptor class A1 repeat domain which is necessary for ligand binding (Sudhof et al., 1985; Rudenko et al., 2002); Reported in ClinVar (ClinVar Variant ID# 226304; ClinVar); This variant is associated with the following publications: (PMID: 17539906, 19062533, 11317361, 11668627, 9259195, 27497240, 16250003, 25463123, 19026292, 14974088, 21925044, 27578104, 27765764, 27824480, 22883975, 17426749, 22836074, 24075752, 21310417, 1301956, 29284604, 19060911, 31447099, 32977124, 32041611, 32719484, 33740630, 34037665, 2988123, 12459547, 23375686) -

Familial hypercholesterolemia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 12, 2017	Variant summary: The LDLR c.81C>G (p.Cys27Trp) variant (alternatively also known as C6W and FH San Francisco) substitutes a Cys residue located in LDL receptor class A repeat which forms ligand binding domain (InterPro, Klancar_2015, Bertolini_2013, Hobbs_1992). The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation (InterPro, PMID: 6091915). Therefore, this variant is predicted to be deleterious for protein function as it breaks down one of the disulphide bonds. 5/5 in silico tools also predict damaging outcome for this variant. This variant was found in 2/121358 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). In literature, this variant is widely reported as a pathogenic variant found mainly in FH patients of European origin (Klancar_2015, Mollaki_2014,Kolansky_2008, Bertolini_2013, Day_1997, Hobbs_1992). Genotype-phenotype correlation study showed that this variant causes a milder disease (Mollaki_2014). A functional study showed that this variant leads to impaired LDL receptor activity (Hobbs_1992). Multiple reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2023	This missense variant (also known as p.Cys6Trp in the mature protein) replaces cysteine with tryptophan at codon 27 in the LDLR type A repeat 1 of the LDLR protein. This variant alters a conserved cysteine residue that is critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study performed with cells from an individual affected with homozygous familial hypercholesterolemia has indicated that the mutant protein retains 15-30% of receptor activity compared with the wild type LDLR protein (PMID: 1301956). This variant has been observed in over 60 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 14974088, 16250003, 23375686, 25463123, 27497240, 27824480, 31345425, 33807407, 34297352). This variant has also been observed in compound heterozygous state in individuals affected with homozygous familial hypercholesterolemia, indicating that this variant contributes to disease (PMID: 19026292, 23375686). This variant has been identified in 4/250746 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Oct 02, 2018	This c.81C>G (p.Cys27Trp) variant in the LDLR gene has been reported in multiple unrelated individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11317361, 11668627, 16250003, 23375686) and is extremely rare in the general population. Functional studies have reported that the mutant LDLR protein retains 15-30% of receptor activity compared with wildtype LDLR protein (PMID: 1301956). Therefore, this c.81C>G (p.Cys27Trp) variant in the LDLR gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 27 of the LDLR protein (p.Cys27Trp). This variant is present in population databases (rs2228671, gnomAD 0.004%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11668627, 14974088, 19026292, 25463123, 27497240, 27824480). This variant is also known as C6W. ClinVar contains an entry for this variant (Variation ID: 226304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). For these reasons, this variant has been classified as Pathogenic. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 05, 2021

ACMG categories: PM1,PM2,PP2,PP4,PP5,BP1 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The p.C27W pathogenic mutation (also known as c.81C>G), located in coding exon 2 of the LDLR gene, results from a C to G substitution at nucleotide position 81. The cysteine at codon 27 is replaced by tryptophan, an amino acid with highly dissimilar properties. Pathogenic LDLR mutations that result in the substitution or generation of cysteine residues within the cysteine-rich LDLR class A repeats and EGF-like domains are common in familial hypercholesterolemia (FH) (Villéger L. Hum Mutat. 2002;20(2):81-7). This particular cysteine alteration has been reported in numerous familial hypercholesterolemia cohorts (e.g., Miltiadous G et al. Hum. Mutat. 2001;17:432-3; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9; Kolansky DM et al. Am. J. Cardiol. 2008;102:1438-43; Mollaki V et al. Atherosclerosis. 2014;237:798-804). Internal structural analysis indicates this alteration eliminates a disulfide bond critical for the structural integrity of LDLR class A repeat 1 (Ambry internal data). Two functional studies have indicated that this alteration leads to reduced LDLR activity, but data were not provided (Hobbs HH et al. Hum. Mutat. 1992;1:445-66; Dedoussis GV et al. Eur. J. Clin. Invest. 2004;34:402-9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.;.;.;.;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;.;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.2	D;D;D;D;D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.91
MutPred		0.83		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		1.0
MPC		0.95
ClinPred		1.0	D
GERP RS		-1.7
Varity_R		0.98
gMVP		1.0

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

LitVar

Other links and lift over

dbSNP: rs2228671; hg19: chr19-11210912;