19-10489261-C-T

Variant names:

• chr19-10489261-C-T
• rs369083385
• NM_203500.2:c.1639G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203500.2(KEAP1):​c.1639G>A​(p.Val547Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000024 in 1,461,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.115073055).
• BS2: High AC in GnomAdExome4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1639G>A	p.Val547Ile	missense_variant	Exon 5 of 6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1639G>A	p.Val547Ile	missense_variant	Exon 5 of 6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1639G>A	p.Val547Ile	missense_variant	Exon 5 of 6	1	NM_203500.2	ENSP00000171111.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 251166 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1461156 Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0088
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.94	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.27
Sift	Benign	0.34	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.15	B;B
Vest4		0.086
MutPred		0.58		Loss of catalytic residue at V547 (P = 0.0107);Loss of catalytic residue at V547 (P = 0.0107);
MVP		0.71
MPC		0.88
ClinPred		0.088	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.12

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

Other links and lift over

dbSNP: rs369083385; hg19: chr19-10599937;