19-10491691-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2BP4_StrongBP6_ModerateBS2

The NM_203500.2(KEAP1):c.1211C>T(p.Ser404Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000629 in 1,572,916 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 1 hom. )

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.74

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP2

Missense variant where missense usually causes diseases, KEAP1

BP4

Computational evidence support a benign effect (MetaRNN=0.014463127).

BP6

Variant 19-10491691-G-A is Benign according to our data. Variant chr19-10491691-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 725487.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	3/6	ENST00000171111.10
KEAP1	NM_012289.4 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KEAP1	ENST00000171111.10 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	3/6	1	NM_203500.2	P1
KEAP1	ENST00000393623.6 linkuse as main transcript	c.1211C>T	p.Ser404Leu	missense_variant	3/6	1		P1
KEAP1	ENST00000592478.5 linkuse as main transcript	c.32C>T	p.Ser11Leu	missense_variant	1/3	1
KEAP1	ENST00000590593.1 linkuse as main transcript	c.191C>T	p.Ser64Leu	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000400

AC:

AN:

199918

Hom.:

AF XY:

0.000277

AC XY:

AN XY:

108476

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00298

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:

0.0000648

AC:

AN:

1420662

Hom.:

Cov.:

AF XY:

0.0000526

AC XY:

AN XY:

703120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000309

Gnomad4 AMR exome

AF:

0.00237

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:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000347

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D

Eigen

Benign

0.018

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.79

M_CAP

Benign

0.016

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

0.99

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.26

Sift

Benign

0.10

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.082

B;B

Vest4

0.22

MutPred

0.51

Loss of disorder (P = 0.0531);Loss of disorder (P = 0.0531);

MVP

0.81

MPC

0.88

ClinPred

0.091

GERP RS

5.8

Varity_R

0.37

gMVP

0.14

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