19-10491504-A-C

Position:

• chr19-10491504-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_203500.2(KEAP1):​c.1325+73T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.929 in 1,290,536 control chromosomes in the GnomAD database, including 557,405 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 0.92 (64654 hom., cov: 31)
  • Exomes 𝑓: 0.93 (492751 hom.)
• Consequence: KEAP1 NM_203500.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KEAP1	NM_203500.2	c.1325+73T>G		intron_variant		ENST00000171111.10	NP_987096.1
KEAP1	NM_012289.4	c.1325+73T>G		intron_variant			NP_036421.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10	c.1325+73T>G		intron_variant		1	NM_203500.2	ENSP00000171111.4
KEAP1	ENST00000393623.6	c.1325+73T>G		intron_variant		1		ENSP00000377245.1
KEAP1	ENST00000592478.5	c.143+73T>G		intron_variant		1		ENSP00000468014.1
KEAP1	ENST00000590593.1	n.302+73T>G		intron_variant		3		ENSP00000467601.1

Frequencies

GnomAD3 genomes AF: 0.921 AC: 140043 AN: 152022 Hom.: 64601 Cov.: 31

Gnomad AFR AF: 0.877

Gnomad AMI AF: 0.957

Gnomad AMR AF: 0.937

Gnomad ASJ AF: 0.912

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.943

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.929

GnomAD4 exome AF: 0.930 AC: 1058866 AN: 1138396 Hom.: 492751 AF XY: 0.931 AC XY: 520362 AN XY: 559110

Gnomad4 AFR exome AF: 0.875

Gnomad4 AMR exome AF: 0.957

Gnomad4 ASJ exome AF: 0.912

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.971

Gnomad4 FIN exome AF: 0.941

Gnomad4 NFE exome AF: 0.926

Gnomad4 OTH exome AF: 0.928

GnomAD4 genome AF: 0.921 AC: 140154 AN: 152140 Hom.: 64654 Cov.: 31 AF XY: 0.924 AC XY: 68703 AN XY: 74368

Gnomad4 AFR AF: 0.877

Gnomad4 AMR AF: 0.937

Gnomad4 ASJ AF: 0.912

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.971

Gnomad4 FIN AF: 0.943

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.929

Alfa AF: 0.930 Hom.: 86691

Bravo AF: 0.918

Asia WGS AF: 0.977 AC: 3397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.79
DANN	Benign	0.38

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: rs11085735; hg19: chr19-10602180;