chr19-10486104-G-A

Variant names:

• chr19-10486104-G-A
• rs9676881
• NM_203500.2:c.*548C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_203500.2(KEAP1):​c.*548C>T variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.458 in 208,742 control chromosomes in the GnomAD database, including 23,969 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 0.48 (18899 hom., cov: 32)
  • Exomes 𝑓: 0.41 (5070 hom.)
• Consequence: KEAP1 NM_203500.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	NM_203500.2	MANE Select	c.*548C>T		downstream_gene	N/A	NP_987096.1
	KEAP1	NM_012289.4		c.*548C>T		downstream_gene	N/A	NP_036421.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KEAP1	ENST00000171111.10	TSL:1 MANE Select	c.*548C>T		downstream_gene	N/A	ENSP00000171111.4
	KEAP1	ENST00000393623.6	TSL:1	c.*548C>T		downstream_gene	N/A	ENSP00000377245.1
	KEAP1	ENST00000592478.5	TSL:1	c.*548C>T		downstream_gene	N/A	ENSP00000468014.1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72107 AN: 151828 Hom.: 18856 Cov.: 32

Gnomad AFR AF: 0.699

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.423

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.374

Gnomad OTH AF: 0.465

GnomAD4 exome AF: 0.412 AC: 23372 AN: 56796 Hom.: 5070 Cov.: 0 AF XY: 0.408 AC XY: 10745 AN XY: 26312

African (AFR) AF: 0.704 AC: 1739 AN: 2470

American (AMR) AF: 0.322 AC: 550 AN: 1708

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1438 AN: 3560

East Asian (EAS) AF: 0.527 AC: 4604 AN: 8728

South Asian (SAS) AF: 0.447 AC: 218 AN: 488

European-Finnish (FIN) AF: 0.342 AC: 13 AN: 38

Middle Eastern (MID) AF: 0.494 AC: 174 AN: 352

European-Non Finnish (NFE) AF: 0.366 AC: 12707 AN: 34758

Other (OTH) AF: 0.411 AC: 1929 AN: 4694

GnomAD4 genome AF: 0.475 AC: 72212 AN: 151946 Hom.: 18899 Cov.: 32 AF XY: 0.475 AC XY: 35247 AN XY: 74270

African (AFR) AF: 0.699 AC: 28981 AN: 41446

American (AMR) AF: 0.354 AC: 5403 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 1466 AN: 3462

East Asian (EAS) AF: 0.551 AC: 2839 AN: 5148

South Asian (SAS) AF: 0.443 AC: 2135 AN: 4820

European-Finnish (FIN) AF: 0.423 AC: 4477 AN: 10574

Middle Eastern (MID) AF: 0.476 AC: 139 AN: 292

European-Non Finnish (NFE) AF: 0.374 AC: 25406 AN: 67954

Other (OTH) AF: 0.469 AC: 989 AN: 2108

Alfa AF: 0.407 Hom.: 44321

Bravo AF: 0.482

Asia WGS AF: 0.508 AC: 1761 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.91
DANN	Benign	0.56
PhyloP100		-0.50
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9676881; hg19: chr19-10596780;