NM_007194.4:c.1420C>T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM5PP3_StrongPP5BS2_Supporting

The NM_007194.4(CHEK2):c.1420C>T(p.Arg474Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,595,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R474H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CHEK2
NM_007194.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:14

Conservation

PhyloP100: 3.16

Publications

25 publications found

Variant links:

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CHEK2 Gene-Disease associations (from GenCC):

CHEK2-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
Li-Fraumeni syndrome 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
acute myeloid leukemia
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CHEK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-28694072-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126910.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 22-28694073-G-A is Pathogenic according to our data. Variant chr22-28694073-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128059.

BS2

High AC in GnomAdExome4 at 30 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHEK2	NM_007194.4 link	c.1420C>T	p.Arg474Cys	missense_variant	Exon 13 of 15	ENST00000404276.6	NP_009125.1	O96017-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHEK2	ENST00000404276.6 link	c.1420C>T	p.Arg474Cys	missense_variant	Exon 13 of 15	1	NM_007194.4	ENSP00000385747.1		O96017-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000171

AC:

AN:

233784

AF XY:

0.0000234

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000276

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000208

AC:

AN:

1443718

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

718616

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.0000447

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1111422

Other (OTH)

AF:

0.00

AC:

AN:

60092

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000131

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000866

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:4

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 14, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: decreased CHEK2 protein expression and impaired kinase activity (PMID: 27900359, 30851065, 37449874); 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; This variant is associated with the following publications: (PMID: 25980754, 26506619, 22138346, 26094658, 19782031, 27900359, 29522266, 29520813, 28580595, 30426508, 29731985, 30851065, 30287823, 30858171, 31398194, 31159747, 33309985, 36061833, 34991090, 35661486, 32980694, 33471991, 36243179, 22419737, 37449874) -

Apr 30, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 04, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population, 0.000028 (3/108758 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 30426508 (2018), 30287823 (2018), 28580595 (2018), and 33471991 (2021)), prostate cancer (PMID: 29520813 (2018)), colorectal cancer (PMID: 33309985 (2020)), as well as in healthy individuals (PMIDs: 32980694 (2020), 33309985 (2020), and 33471991 (2021)). Additionally, the variant was reported in an individual with suspected Lynch Syndrome (PMID: 25980754 (2015)). Yeast-based and mammalian studies have reported that this variant may have a deleterious effect on CHEK2 protein function. Further studies are needed to validate these findings (PMIDs: 27900359 (2016) and 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHEK2: PS3, PM1, PM5:Supporting -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:3

Aug 01, 2018

GeneKor MSA

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 24, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 474 of the CHEK2 protein. This variant impacts a highly conserved arginine in the kinase domain of the protein (PMID: 15060014, 19782031). Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant may impact CHEK2 kinase activity and DNA damage response (PMID: 30851065, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 28580595, 29522266, 30287823, 30426508, 34991090) and is found in breast cancer case-control meta-analyses in (PMID: 33471991, 37449874) but the finding have yet to achieve statistical significance. This variant has been identified in 4/233784 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R474C variant (also known as c.1420C>T), located in coding exon 12 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1420. The arginine at codon 474 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in the homozygous state in siblings with multiple primary lung cancers; the sister was also affected with breast cancer and uterine myoma and the brother was also affected with prostate and colon cancers (Kukita Y et al Cold Spring Harb. Mol. Case Stud. 2016 Nov;2(6):a001032). In addition, this alteration has been reported in the heterozygous state in multiple cohorts of affected patients with various tumor types (Wu Y et al. Prostate. 2018 Jun;78(8):607-615; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Schubert S et al. Int. J. Cancer 2019 06;144(11):2683-2694; Xie Y et al. Clin. Genet. 2018 Jan;93(1):41-51; Tsaousis GN et al. BMC Cancer 2019 Jun;19(1):535; Dorling et al. N Engl J Med. 2021 02;384:428-439; Aksoy F et al. Hum Hered, 2022 Jan;:). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40(5):631-648). In addition, this alteration was reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). The p.R474C variant has been shown to eliminate a salt bridge between the core kinase domain and the highly conserved activation loop, and is critical for stability and function of Ser/Thr kinases (Ambry internal analysis; Cai Z et al. Mol. Cell. 2009 Sep;35:818-29; Yang J et al. J. Mol. Biol. 2012 Jan;415:666-79). 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 limited at this time, the clinical significance of this alteration remains unclear. -

Sep 22, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM1, PM2_Supporting c.1420C>T, located in exon 13 of the CHEK2 gene, is predicted to result in the substitution of arginine to cysteine at codon 474, p.(Arg474Cys).This variant affects a highly conserved amino acid of the kinase-domain (226-486 aa)(PM1). This variant is found in 4/253791 at a frequency of 0.0026% in the gnomAD v2.1.1 database (European non-Finnish non-cancer data set)(PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.903) for this variant suggests a deleterious effect on protein function according Pejaver 2022 thresholds (PMID: 36413997). The variant is present in ClinVar (11x uncertain significance, 6x likely pathogenic) and LOVD (3x VUS, 2x not classified) databases. Experimental studies showed a pathogenic effect on KAP1 phosphorylation intensity and an deleterious effect on autophosphorylation of CHK2 in in human RPE1-CHEK2-knockout cells (PMID: 30851065, PMID: 37449874)(PS3). Moreover, other variant that disrupt this residue has been determined to be likely pathogenic, c.1421G>A; p.(Arg474His). Based on currently available information, the variant c.1420C>T is classified as a likely pathogenic variant according to ACMG guidelines. -

Familial cancer of breast

Pathogenic:1Uncertain:3

Jun 28, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27900359]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. -

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the CHEK2 protein (p.Arg474Cys). This variant is present in population databases (rs540635787, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer, lung cancer, Lynch syndrome-associated cancer(s), and/or prostate cancer (PMID: 25980754, 27900359, 28580595, 29520813, 30287823, 30426508, 33309985). This variant is also known as c.1549C>T (p.Arg517Cys). ClinVar contains an entry for this variant (Variation ID: 128059). 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 CHEK2 function (PMID: 27900359, 30851065). 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. -

May 30, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CHEK2-related cancer predisposition

Pathogenic:1Uncertain:2

May 01, 2023

Department of Genetics, HCU Lozano Blesa

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Variant summary: CHEK2 c.1420C>T results in the replacement of Arg474 by a Cys residue (p.Arg474Cys). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a woman that developed breast cancer at the age of 69 years (luminal-A tumor phenotype). Two second-degree relatives were also diagnosed with BC, although a co-segregation study could not be performed. Arg474 is located in the kinase domain and appears well conserved in vertebrate species. The replacement of Arg474 by a cysteine could affect the interaction with some residues at the dimerization interface, particularly with Ala392. It thus may affect the protein integrity and therefore its function. In addition, Arg474, forms a cation/π interaction with Trp411 (at the same monomer) and a salt bridge with Glu394 (at the partner monomer). Replacement of Arg474 with a cysteine residue will therefore remove the indicated stabilizing interactions of Arg474. The variant is reported in gnomAD v4 in 32 cases out of 1595950 alleles analysed (freq=2.0x10-3 %). In ClinVar a dozen of reports appear classifying the variant as of Uncertain Significance, whereas in 3 reports the submitters have suggested the classification of Likely Pathogenic. Other replacements found at this position (R474L, R474G, R474S and R474H) are classified by ClinVar as of either Uncertain Significance or Conflicting Interpretation. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) and the AI-based predictor AlphaMissense classify Arg474Cys as Pathogenic, whereas the ACMG classification tool Franklin suggests this variant as Likely Pathogenic. Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that Arg474Cys induces conformational unstability on CHEK2 protein. Moreover, Stolarova L. et al’s functional study on KAP1 phosphorylation and CHEK2 autophosphorylation protein capability reports this variant as functionally impaired (PMID: 37449874). In summary, we believe this variant have more chances of being Pathogenic. -

Jan 06, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 474 of the CHEK2 protein (p.Arg474Cys). This variant is present in population databases (rs540635787, gnomAD 0.003%). This amino acid position is highly conserved. This missense change has been observed in individual(s) with breast cancer, lung cancer, Lynch syndrome-associated cancer(s), and/or prostate cancer (PMID: 25980754, 27900359, 28580595, 29520813, 30287823, 30426508, 33309985). This variant is also known as c.1549C>T (p.Arg517Cys). ClinVar contains an entry for this variant (Variation ID: 128059) with nine submission as Uncertain significance and four submission as likely pathogenic. In addition, this alteration is predicted to be deleterious by in silico analysis. 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. -

Apr 22, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial cancer of breast;C0376358:Prostate cancer;C0684249:Lung carcinoma;C0699790:Carcinoma of colon

Pathogenic:1

Department of Molecular and Medical Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Two siblings, an elder sister and a younger brother, were found to have multiple primary lung cancers at the age of 60. The former subsequently developed breast cancer, and had a history of myoma uteri. The latter had initially developed prostate cancer at the age of 59, and had a history of colon cancer. This variant was homozygous in both patients. -

not specified

Uncertain:1

Mar 16, 2022

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: CHEK2 c.1420C>T (p.Arg474Cys) results in a non-conservative amino acid change located in the protein kinase-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant reportedly alters the tertiary structure of CHEK2 by disrupting the salt bridge between p.R474 and p.E394 suggesting that protein stability of both inactive and active states might be disturbed (Kukita_2016, Delimitsou_2019). The variant allele was found at a frequency of 1.7e-05 in 233784 control chromosomes (gnomAD). It has also been reported in the FLOSSIES database of women over the age of 70 with no history of cancer. c.1420C>T has been reported in the literature in individuals affected with a a variety of cancer types such as colorectal cancer, prostate cancer, breast cancer and lung cancer (e.g. Kukita_2016, Wu_2016, Schubert_2019), including two homozygous siblings who experienced multiple primary lung cancers as well as cancers in other organs (Kukita_2016). These data indicate that the variant may be associated with disease. The variant was determined to be damaging in an in vivo yeast functional assay (Delimitsou_2019). Kukita_2016 also found the variant expression protein did not increase nor activate in response to UV damage. Nine ClinVar submitters have assessed this variant since 2014: eight classified the variant as of uncertain significance and one as likely pathogenic. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Familial cancer of breast;C0376358:Prostate cancer;C0585442:Bone osteosarcoma;C5882668:CHEK2-related cancer predisposition

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

D;.;D;.;D;.;D;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.98

.;D;.;D;.;D;D;D;.

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.8

H;.;H;.;H;.;H;.;.

PhyloP100

3.2

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-7.4

D;D;D;.;D;D;.;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D;.;D;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;.;D;D;.;D;D

Polyphen

1.0

D;D;D;.;D;D;D;D;D

Vest4

0.96

MutPred

0.98

Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);.;Loss of disorder (P = 0.0362);.;.;

MVP

0.95

MPC

0.16

ClinPred

1.0

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.94

Mutation Taster

=3/97

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over