19-10489724-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_203500.2(KEAP1):c.1455T>G(p.Asn485Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

KEAP1
NM_203500.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.371

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, KEAP1

BP4

Computational evidence support a benign effect (MetaRNN=0.2559368).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2 linkuse as main transcript	c.1455T>G	p.Asn485Lys	missense_variant	4/6	ENST00000171111.10
KEAP1	NM_012289.4 linkuse as main transcript	c.1455T>G	p.Asn485Lys	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KEAP1	ENST00000171111.10 linkuse as main transcript	c.1455T>G	p.Asn485Lys	missense_variant	4/6	1	NM_203500.2	P1
KEAP1	ENST00000393623.6 linkuse as main transcript	c.1455T>G	p.Asn485Lys	missense_variant	4/6	1		P1
KEAP1	ENST00000592478.5 linkuse as main transcript	c.276T>G	p.Asn92Lys	missense_variant	2/3	1
KEAP1	ENST00000590593.1 linkuse as main transcript	c.305-356T>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

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

Jul 09, 2021

The c.1455T>G (p.N485K) alteration is located in exon 4 (coding exon 3) of the KEAP1 gene. This alteration results from a T to G substitution at nucleotide position 1455, causing the asparagine (N) at amino acid position 485 to be replaced by a lysine (K). 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

0.23

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Benign

0.89

DEOGEN2

Benign

0.41

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.74

M_CAP

Benign

0.029

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.80

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.16

Sift

Benign

0.15

T;T

Sift4G

Benign

0.42

T;T

Polyphen

0.11

B;B

Vest4

0.19

MutPred

0.60

Gain of ubiquitination at N485 (P = 0.0146);Gain of ubiquitination at N485 (P = 0.0146);

MVP

0.65

MPC

1.6

ClinPred

0.056

GERP RS

-0.73

Varity_R

0.26

gMVP

0.36

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

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