rs11545829

chr19-10489289-G-Achr19-10489289-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_203500.2(KEAP1):c.1611C>T(p.Tyr537=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 1,613,870 control chromosomes in the GnomAD database, including 2,481 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (266 hom., cov: 31)
  • Exomes 𝑓: 0.016 (2215 hom.)
• Consequence: KEAP1 NM_203500.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.263

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=-0.263 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2	c.1611C>T	p.Tyr537=	synonymous_variant	5/6	ENST00000171111.10
KEAP1	NM_012289.4	c.1611C>T	p.Tyr537=	synonymous_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KEAP1	ENST00000171111.10	c.1611C>T	p.Tyr537=	synonymous_variant	5/6	1	NM_203500.2	P1

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3096 AN: 151938 Hom.: 265 Cov.: 31

Gnomad AFR AF: 0.00792

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.0672

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0207

GnomAD3 exomes AF: 0.0416 AC: 10465 AN: 251306 Hom.: 951 AF XY: 0.0390 AC XY: 5297 AN XY: 135854

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.0839

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.0543

Gnomad FIN exome AF: 0.00300

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0156 AC: 22857 AN: 1461814 Hom.: 2215 Cov.: 33 AF XY: 0.0163 AC XY: 11861 AN XY: 727208

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.0818

Gnomad4 ASJ exome AF: 0.00585

Gnomad4 EAS exome AF: 0.293

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.00270

Gnomad4 NFE exome AF: 0.000701

Gnomad4 OTH exome AF: 0.0261

GnomAD4 genome AF: 0.0204 AC: 3109 AN: 152056 Hom.: 266 Cov.: 31 AF XY: 0.0229 AC XY: 1702 AN XY: 74322

Gnomad4 AFR AF: 0.00800

Gnomad4 AMR AF: 0.0512

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.0671

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0209

Alfa AF: 0.00890 Hom.: 169

Bravo AF: 0.0261

Asia WGS AF: 0.166 AC: 574 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.12
Dann	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11545829; hg19: chr19-10599965; COSMIC: COSV50266753; COSMIC: COSV50266753;