chr19-10491910-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_203500.2(KEAP1):c.992C>T(p.Ala331Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
KEAP1
NM_203500.2 missense
NM_203500.2 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 3.28
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, KEAP1
BS2
?
High AC in GnomAdExome at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KEAP1 | NM_203500.2 | c.992C>T | p.Ala331Val | missense_variant | 3/6 | ENST00000171111.10 | |
KEAP1 | NM_012289.4 | c.992C>T | p.Ala331Val | missense_variant | 3/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KEAP1 | ENST00000171111.10 | c.992C>T | p.Ala331Val | missense_variant | 3/6 | 1 | NM_203500.2 | P1 | |
KEAP1 | ENST00000393623.6 | c.992C>T | p.Ala331Val | missense_variant | 3/6 | 1 | P1 | ||
KEAP1 | ENST00000590593.1 | upstream_gene_variant | 3 | ||||||
KEAP1 | ENST00000588024.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152256Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248650Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135064
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461272Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 726950
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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 | Mar 20, 2023 | The c.992C>T (p.A331V) alteration is located in exon 3 (coding exon 2) of the KEAP1 gene. This alteration results from a C to T substitution at nucleotide position 992, causing the alanine (A) at amino acid position 331 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
D;D
Vest4
MutPred
Loss of catalytic residue at A331 (P = 0.0612);Loss of catalytic residue at A331 (P = 0.0612);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at