19-10489766-G-C

Variant names:

• chr19-10489766-G-C
• rs1048290
• NM_203500.2:c.1413C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_203500.2(KEAP1):​c.1413C>G​(p.Leu471Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 56 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• 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 rank	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1413C>G	p.Leu471Leu	synonymous_variant	Exon 4 of 6	ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1413C>G	p.Leu471Leu	synonymous_variant	Exon 4 of 6		NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1413C>G	p.Leu471Leu	synonymous_variant	Exon 4 of 6	1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1413C>G	p.Leu471Leu	synonymous_variant	Exon 4 of 6	1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.231C>G	p.Leu77Leu	synonymous_variant	Exon 2 of 3	1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.303-398C>G		intron_variant	Intron 1 of 2	3		ENSP00000467601.1

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

GnomAD2 exomes AF: 0.412 AC: 103520 AN: 251116 AF XY: 0.409

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 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

African (AFR) AF: 0.704 AC: 23579 AN: 33476

American (AMR) AF: 0.314 AC: 14045 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 10552 AN: 26134

East Asian (EAS) AF: 0.499 AC: 19818 AN: 39684

South Asian (SAS) AF: 0.442 AC: 38136 AN: 86250

European-Finnish (FIN) AF: 0.409 AC: 21839 AN: 53402

Middle Eastern (MID) AF: 0.496 AC: 2858 AN: 5764

European-Non Finnish (NFE) AF: 0.371 AC: 412034 AN: 1111924

Other (OTH) AF: 0.413 AC: 24929 AN: 60392

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

African (AFR) AF: 0.693 AC: 28718 AN: 41438

American (AMR) AF: 0.355 AC: 5397 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 1462 AN: 3470

East Asian (EAS) AF: 0.535 AC: 2755 AN: 5146

South Asian (SAS) AF: 0.444 AC: 2135 AN: 4808

European-Finnish (FIN) AF: 0.422 AC: 4442 AN: 10522

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.371 AC: 25202 AN: 67928

Other (OTH) AF: 0.468 AC: 988 AN: 2112

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
PhyloP100		0.081
Mutation Taster		=100/0	polymorphism (auto)

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

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