Genetic Variant KLK1:p.Lys186Glu (chr19-50819976-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002257.4(KLK1):c.556A>G(p.Lys186Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,644 control chromosomes in the GnomAD database, including 70,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6484 hom., cov: 32)

Exomes 𝑓: 0.29 ( 64389 hom. )

Consequence

KLK1
NM_002257.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.951

Publications

46 publications found

Variant links:

Genes affected

KLK1 (HGNC:6357): (kallikrein 1) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. This protein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular weight kininogen. [provided by RefSeq, Jul 2008]

KLK1 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

KLK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.245634E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK1	NM_002257.4 link	c.556A>G	p.Lys186Glu	missense_variant	Exon 4 of 5	ENST00000301420.3	NP_002248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK1	ENST00000301420.3 link	c.556A>G	p.Lys186Glu	missense_variant	Exon 4 of 5	1	NM_002257.4	ENSP00000301420.1

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42156

AN:

152034

Hom.:

6462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.395

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.586

Gnomad SAS

AF:

0.283

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.273

GnomAD2 exomes

AF:

0.329

AC:

82611

AN:

251246

AF XY:

0.318

show subpopulations

Gnomad AFR exome

AF:

0.199

Gnomad AMR exome

AF:

0.527

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.587

Gnomad FIN exome

AF:

0.304

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.296

GnomAD4 exome

AF:

0.289

AC:

421873

AN:

1461492

Hom.:

64389

Cov.:

AF XY:

0.287

AC XY:

208566

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.192

AC:

6438

AN:

33478

American (AMR)

AF:

0.510

AC:

22774

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.249

AC:

6504

AN:

26130

East Asian (EAS)

AF:

0.530

AC:

21020

AN:

39692

South Asian (SAS)

AF:

0.275

AC:

23759

AN:

86246

European-Finnish (FIN)

AF:

0.305

AC:

16286

AN:

53412

Middle Eastern (MID)

AF:

0.223

AC:

1283

AN:

5766

European-Non Finnish (NFE)

AF:

0.276

AC:

306274

AN:

1111684

Other (OTH)

AF:

0.290

AC:

17535

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

15494

30988

46481

61975

77469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10472

20944

31416

41888

52360

<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:

0.277

AC:

42218

AN:

152152

Hom.:

6484

Cov.:

AF XY:

0.282

AC XY:

20955

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.197

AC:

8161

AN:

41506

American (AMR)

AF:

0.396

AC:

6063

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

929

AN:

3472

East Asian (EAS)

AF:

0.586

AC:

3023

AN:

5162

South Asian (SAS)

AF:

0.283

AC:

1366

AN:

4822

European-Finnish (FIN)

AF:

0.303

AC:

3214

AN:

10594

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.274

AC:

18620

AN:

67984

Other (OTH)

AF:

0.282

AC:

594

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1528

3056

4584

6112

7640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.277

Hom.:

18108

Bravo

AF:

0.284

TwinsUK

AF:

0.279

AC:

1034

ALSPAC

AF:

0.265

AC:

1023

ESP6500AA

AF:

0.196

AC:

865

ESP6500EA

AF:

0.269

AC:

2310

ExAC

AF:

0.320

AC:

38800

Asia WGS

AF:

0.445

AC:

1547

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

8.4

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.13

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.042

MetaRNN

Benign

0.0000082

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.070

PhyloP100

-0.95

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.13

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.033

ClinPred

0.0024

GERP RS

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.46

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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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