19-10486696-C-A

Variant names:

• chr19-10486696-C-A
• NM_203500.2:c.1831G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_203500.2(KEAP1):​c.1831G>T​(p.Glu611*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KEAP1 NM_203500.2 stop_gained
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 7.06
• Publications: 0 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.

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

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.1831G>T	p.Glu611*	stop_gained	Exon 6 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.1831G>T	p.Glu611*	stop_gained	Exon 6 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.1831G>T	p.Glu611*	stop_gained	Exon 6 of 6	ENSP00000171111.4	Q14145
	KEAP1	ENST00000393623.6	TSL:1	c.1831G>T	p.Glu611*	stop_gained	Exon 6 of 6	ENSP00000377245.1	Q14145
	KEAP1	ENST00000592478.5	TSL:1	c.472G>T	p.Glu158*	stop_gained	Exon 3 of 3	ENSP00000468014.1	K7EQX2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.90	D
PhyloP100		7.1
Vest4		0.80
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=16/184	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

hg19: chr19-10597372;