19-10491796-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_203500.2(KEAP1):c.1106T>C(p.Val369Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,590,412 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: KEAP1 NM_203500.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.33

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KEAP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0135143995).
• BP6: Variant 19-10491796-A-G is Benign according to our data. Variant chr19-10491796-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 726614.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 161 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KEAP1	NM_203500.2	c.1106T>C	p.Val369Ala	missense_variant	3/6	ENST00000171111.10
KEAP1	NM_012289.4	c.1106T>C	p.Val369Ala	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KEAP1	ENST00000171111.10	c.1106T>C	p.Val369Ala	missense_variant	3/6	1	NM_203500.2	P1
KEAP1	ENST00000393623.6	c.1106T>C	p.Val369Ala	missense_variant	3/6	1		P1
KEAP1	ENST00000590593.1	c.86T>C	p.Val29Ala	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00109 AC: 225 AN: 205716 Hom.: 0 AF XY: 0.00120 AC XY: 135 AN XY: 112372

Gnomad AFR exome AF: 0.0000814

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000287

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.00134 AC: 1926 AN: 1438084 Hom.: 2 Cov.: 32 AF XY: 0.00130 AC XY: 929 AN XY: 713598

Gnomad4 AFR exome AF: 0.0000915

Gnomad4 AMR exome AF: 0.000444

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000262

Gnomad4 FIN exome AF: 0.000176

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74488

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00130 AC: 11

ExAC AF: 0.000821 AC: 98

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.0091	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Benign	0.080
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.78	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.13	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.18	B;B
Vest4		0.42
MVP		0.88
MPC		1.3
ClinPred		0.024	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.50
gMVP		0.52

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: rs149721624; hg19: chr19-10602472; COSMIC: COSV50290796; COSMIC: COSV50290796;