rs1048290

Positions:

• chr19-10489766-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_203500.2(KEAP1):​c.1413C>G​(p.Leu471=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,613,584 control chromosomes in the GnomAD database, including 132,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.47 (18584 hom., cov: 31)
  • Exomes 𝑓: 0.39 (113478 hom.)
• Consequence: KEAP1 NM_203500.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0810

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 19-10489766-G-C is Benign according to our data. Variant chr19-10489766-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2	c.1413C>G	p.Leu471=	synonymous_variant	4/6	ENST00000171111.10
KEAP1	NM_012289.4	c.1413C>G	p.Leu471=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KEAP1	ENST00000171111.10	c.1413C>G	p.Leu471=	synonymous_variant	4/6	1	NM_203500.2	P1
KEAP1	ENST00000393623.6	c.1413C>G	p.Leu471=	synonymous_variant	4/6	1		P1
KEAP1	ENST00000592478.5	c.234C>G	p.Leu78=	synonymous_variant	2/3	1
KEAP1	ENST00000590593.1	c.305-398C>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.471 AC: 71514 AN: 151720 Hom.: 18544 Cov.: 31

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.412 AC: 103520 AN: 251116 Hom.: 22640 AF XY: 0.409 AC XY: 55565 AN XY: 135746

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.309

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.532

Gnomad SAS exome AF: 0.446

Gnomad FIN exome AF: 0.414

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.388 AC: 567790 AN: 1461744 Hom.: 113478 Cov.: 49 AF XY: 0.389 AC XY: 282642 AN XY: 727170

Gnomad4 AFR exome AF: 0.704

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.409

Gnomad4 NFE exome AF: 0.371

Gnomad4 OTH exome AF: 0.413

GnomAD4 genome AF: 0.472 AC: 71615 AN: 151840 Hom.: 18584 Cov.: 31 AF XY: 0.471 AC XY: 34953 AN XY: 74186

Gnomad4 AFR AF: 0.693

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.444

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.371

Gnomad4 OTH AF: 0.468

Alfa AF: 0.397 Hom.: 4070

Bravo AF: 0.478

Asia WGS AF: 0.492 AC: 1708 AN: 3478

EpiCase AF: 0.385

EpiControl AF: 0.373

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.4
DANN	Benign	0.40

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: rs1048290; hg19: chr19-10600442; COSMIC: COSV50260426; COSMIC: COSV50260426;