19-10489771-G-T

Variant names:

• chr19-10489771-G-T
• NM_203500.2:c.1408C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_203500.2(KEAP1):​c.1408C>A​(p.Arg470Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as other (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1408C>A	p.Arg470Ser	missense_variant	Exon 4 of 6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1408C>A	p.Arg470Ser	missense_variant	Exon 4 of 6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1408C>A	p.Arg470Ser	missense_variant	Exon 4 of 6	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1408C>A	p.Arg470Ser	missense_variant	Exon 4 of 6	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.226C>A	p.Arg76Ser	missense_variant	Exon 2 of 3	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.303-403C>A		intron_variant	Intron 1 of 2	3		ENSP00000467601.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

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	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.30	N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.20	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.99	D;D
Vest4		0.58
MutPred		0.57		Loss of MoRF binding (P = 0.0138);Loss of MoRF binding (P = 0.0138);
MVP		0.94
MPC		2.1
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.83
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10600447; COSMIC: COSV50262012; COSMIC: COSV50262012;