Genetic Variant NM_203500.2:c.474T>C (chr19-10499560-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -5.24

Publications

24 publications found

Variant links:

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

KEAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KEAP1	NM_203500.2 link	c.474T>C	p.Gly158Gly	synonymous_variant	Exon 2 of 6	ENST00000171111.10	NP_987096.1	Q14145A0A024R7C0
KEAP1	NM_012289.4 link	c.474T>C	p.Gly158Gly	synonymous_variant	Exon 2 of 6		NP_036421.2	Q14145A0A024R7C0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KEAP1	ENST00000171111.10 link	c.474T>C	p.Gly158Gly	synonymous_variant	Exon 2 of 6	1	NM_203500.2	ENSP00000171111.4		Q14145

Frequencies

GnomAD3 genomes

AF:

0.110

AC:

16698

AN:

152172

Hom.:

1086

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0878

AC XY:

63869

AN XY:

727174

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

7879

15757

23636

31514

39393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3900

7800

11700

15600

19500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.110

AC:

16726

AN:

152290

Hom.:

1092

Cov.:

AF XY:

0.108

AC XY:

8077

AN XY:

74462

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0907

AC:

6172

AN:

68026

Other (OTH)

AF:

0.110

AC:

233

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

780

1560

2341

3121

3901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

178

356

534

712

890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.20

(source)

DANN

Benign

0.52

PhyloP100

-5.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over