19-10489686-C-G

Variant names:

• chr19-10489686-C-G
• rs1281598803
• NM_203500.2:c.1493G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_203500.2(KEAP1):​c.1493G>C​(p.Arg498Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0490
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

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.1493G>C	p.Arg498Pro	missense	Exon 4 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1493G>C	p.Arg498Pro	missense	Exon 4 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.1493G>C	p.Arg498Pro	missense	Exon 4 of 6	ENSP00000171111.4	Q14145
	KEAP1	ENST00000393623.6	TSL:1	c.1493G>C	p.Arg498Pro	missense	Exon 4 of 6	ENSP00000377245.1	Q14145
	KEAP1	ENST00000592478.5	TSL:1	c.311G>C	p.Arg104Pro	missense	Exon 2 of 3	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.049
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.55
Sift	Benign	0.22	T
Sift4G	Benign	0.27	T
Polyphen		0.90	P
Vest4		0.74
MutPred		0.65		Loss of MoRF binding (P = 0.0143)
MVP		0.90
MPC		1.8
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.76
gMVP		0.83
Mutation Taster		=50/50

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

Other links and lift over

dbSNP: rs1281598803; hg19: chr19-10600362;