19-10499560-A-G

Variant names:

• chr19-10499560-A-G
• rs1048287
• NM_203500.2:c.474T>C

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.474T>C​(p.Gly158Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,614,064 control chromosomes in the GnomAD database, including 7,612 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 0.11 (1092 hom., cov: 32)
  • Exomes 𝑓: 0.090 (6520 hom.)
• Consequence: KEAP1 NM_203500.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.24
• Publications: 24 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=-0.83).
• BP7: Synonymous conserved (PhyloP=-5.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

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.474T>C	p.Gly158Gly	synonymous	Exon 2 of 6	NP_987096.1	Q14145
	KEAP1	NM_012289.4		c.474T>C	p.Gly158Gly	synonymous	Exon 2 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.474T>C	p.Gly158Gly	synonymous	Exon 2 of 6	ENSP00000171111.4	Q14145
	KEAP1	ENST00000393623.6	TSL:1	c.474T>C	p.Gly158Gly	synonymous	Exon 2 of 6	ENSP00000377245.1	Q14145
	KEAP1	ENST00000953686.1		c.474T>C	p.Gly158Gly	synonymous	Exon 2 of 7	ENSP00000623745.1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16698 AN: 152172 Hom.: 1086 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.0738

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0252

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0907

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0798 AC: 19986 AN: 250442 AF XY: 0.0770

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0945

Gnomad OTH exome AF: 0.0802

GnomAD4 exome AF: 0.0902 AC: 131823 AN: 1461774 Hom.: 6520 Cov.: 32 AF XY: 0.0878 AC XY: 63869 AN XY: 727174

African (AFR) AF: 0.183 AC: 6127 AN: 33478

American (AMR) AF: 0.0515 AC: 2305 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 2029 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0263 AC: 2272 AN: 86258

European-Finnish (FIN) AF: 0.127 AC: 6780 AN: 53324

Middle Eastern (MID) AF: 0.0917 AC: 529 AN: 5768

European-Non Finnish (NFE) AF: 0.0957 AC: 106449 AN: 1111994

Other (OTH) AF: 0.0882 AC: 5327 AN: 60396

GnomAD4 genome AF: 0.110 AC: 16726 AN: 152290 Hom.: 1092 Cov.: 32 AF XY: 0.108 AC XY: 8077 AN XY: 74462

African (AFR) AF: 0.176 AC: 7317 AN: 41554

American (AMR) AF: 0.0763 AC: 1166 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0738 AC: 256 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0252 AC: 122 AN: 4834

European-Finnish (FIN) AF: 0.126 AC: 1337 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0907 AC: 6172 AN: 68026

Other (OTH) AF: 0.110 AC: 233 AN: 2116

Alfa AF: 0.0974 Hom.: 1455

Bravo AF: 0.112

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0918

EpiControl AF: 0.0958

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.20
DANN	Benign	0.52
PhyloP100		-5.2
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: rs1048287; hg19: chr19-10610236; COSMIC: COSV50270216; COSMIC: COSV50270216;