Variant 19-10489198-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2

The NM_203500.2(KEAP1):c.1702G>A(p.Val568Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,459,630 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.58

Variant links:

Genes affected

KEAP1 (HGNC:23177): (kelch like ECH associated protein 1) This gene encodes a protein containing KELCH-1 like domains, as well as a BTB/POZ domain. Kelch-like ECH-associated protein 1 interacts with NF-E2-related factor 2 in a redox-sensitive manner and the dissociation of the proteins in the cytoplasm is followed by transportation of NF-E2-related factor 2 to the nucleus. This interaction results in the expression of the catalytic subunit of gamma-glutamylcysteine synthetase. Two alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

KEAP1 links:

KEAP1 (HGNC:):

KEAP1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KEAP1. . Gene score misZ 3.7962 (greater than the threshold 3.09). Trascript score misZ 4.2882 (greater than threshold 3.09). GenCC has associacion of gene with goiter, multinodular 1, with or without Sertoli-Leydig cell tumors.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEAP1	NM_203500.2 linkuse as main transcript	c.1702G>A	p.Val568Ile	missense_variant	5/6	ENST00000171111.10	NP_987096.1	Q14145A0A024R7C0
KEAP1	NM_012289.4 linkuse as main transcript	c.1702G>A	p.Val568Ile	missense_variant	5/6		NP_036421.2	Q14145A0A024R7C0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10 linkuse as main transcript	c.1702G>A	p.Val568Ile	missense_variant	5/6	1	NM_203500.2	ENSP00000171111.4		Q14145

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250678

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1459630

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726104

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2024

The c.1702G>A (p.V568I) alteration is located in exon 5 (coding exon 4) of the KEAP1 gene. This alteration results from a G to A substitution at nucleotide position 1702, causing the valine (V) at amino acid position 568 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.88

N;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.32

MutPred

0.56

Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);

MVP

0.85

MPC

1.4

ClinPred

0.69

GERP RS

5.6

Varity_R

0.40

gMVP

0.45

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over