19-10486666-TCTG-T

Position:

• chr19-10486666-TCTG-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PM4_Supporting BP6_Moderate BS2

The NM_203500.2(KEAP1):​c.1858_1860del​(p.Gln620del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00332 in 1,614,072 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (13 hom.)
• Consequence: KEAP1 NM_203500.2 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.04

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 -5 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_203500.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-10486666-TCTG-T is Benign according to our data. Variant chr19-10486666-TCTG-T is described in ClinVar as [Likely_benign]. Clinvar id is 773348.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2	c.1858_1860del	p.Gln620del	inframe_deletion	6/6	ENST00000171111.10
KEAP1	NM_012289.4	c.1858_1860del	p.Gln620del	inframe_deletion	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KEAP1	ENST00000171111.10	c.1858_1860del	p.Gln620del	inframe_deletion	6/6	1	NM_203500.2	P1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00213 AC: 535 AN: 251004 Hom.: 1 AF XY: 0.00220 AC XY: 298 AN XY: 135612

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00346 AC: 5065 AN: 1461836 Hom.: 13 AF XY: 0.00338 AC XY: 2460 AN XY: 727222

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00301

Gnomad4 NFE exome AF: 0.00429

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.00189 AC XY: 141 AN XY: 74430

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.00181

EpiCase AF: 0.00262

EpiControl AF: 0.00344

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs559787043; hg19: chr19-10597342;