NM_203500.2:c.1258G>C

Variant names:

• chr19-10491644-C-G
• rs1199464053
• NM_203500.2:c.1258G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_203500.2(KEAP1):​c.1258G>C​(p.Val420Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,594,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• goiter, multinodular 1, with or without Sertoli-Leydig cell tumors

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203500.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	NM_203500.2	MANE Select	c.1258G>C	p.Val420Leu	missense	Exon 3 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1258G>C	p.Val420Leu	missense	Exon 3 of 6	NP_036421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	ENST00000171111.10	TSL:1 MANE Select	c.1258G>C	p.Val420Leu	missense	Exon 3 of 6	ENSP00000171111.4	Q14145
	KEAP1	ENST00000393623.6	TSL:1	c.1258G>C	p.Val420Leu	missense	Exon 3 of 6	ENSP00000377245.1	Q14145
	KEAP1	ENST00000592478.5	TSL:1	c.76G>C	p.Val26Leu	missense	Exon 1 of 3	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228634 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000317

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000139 AC: 2 AN: 1441834 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715894

African (AFR) AF: 0.00 AC: 0 AN: 32976

American (AMR) AF: 0.0000480 AC: 2 AN: 41700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24728

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 82978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102734

Other (OTH) AF: 0.00 AC: 0 AN: 59520

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.000262 AC: 4 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.92	P
Vest4		0.74
MutPred		0.72		Gain of sheet (P = 0.1451)
MVP		0.91
MPC		1.1
ClinPred		0.89	D
GERP RS		5.6
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.73
gMVP		0.58
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs1199464053; hg19: chr19-10602320;