19-50820217-C-G

Variant summary

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

The NM_002257.4(KLK1):​c.433G>C​(p.Glu145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,611,396 control chromosomes in the GnomAD database, including 370,666 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 0.67 ( 34332 hom., cov: 31)
Exomes 𝑓: 0.68 ( 336334 hom. )

Consequence

KLK1
NM_002257.4 missense

Scores

18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.07

Publications

58 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

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=1.1316266E-6).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLK1NM_002257.4 linkc.433G>C p.Glu145Gln missense_variant Exon 3 of 5 ENST00000301420.3 NP_002248.1 P06870-1A0A1R3UCD2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLK1ENST00000301420.3 linkc.433G>C p.Glu145Gln missense_variant Exon 3 of 5 1 NM_002257.4 ENSP00000301420.1 P06870-1

Frequencies

GnomAD3 genomes
AF:
0.670
AC:
101698
AN:
151762
Hom.:
34293
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.637
Gnomad AMI
AF:
0.644
Gnomad AMR
AF:
0.728
Gnomad ASJ
AF:
0.628
Gnomad EAS
AF:
0.795
Gnomad SAS
AF:
0.656
Gnomad FIN
AF:
0.663
Gnomad MID
AF:
0.611
Gnomad NFE
AF:
0.672
Gnomad OTH
AF:
0.681
GnomAD2 exomes
AF:
0.689
AC:
172940
AN:
251044
AF XY:
0.682
show subpopulations
Gnomad AFR exome
AF:
0.636
Gnomad AMR exome
AF:
0.801
Gnomad ASJ exome
AF:
0.617
Gnomad EAS exome
AF:
0.792
Gnomad FIN exome
AF:
0.672
Gnomad NFE exome
AF:
0.672
Gnomad OTH exome
AF:
0.676
GnomAD4 exome
AF:
0.677
AC:
988384
AN:
1459514
Hom.:
336334
Cov.:
56
AF XY:
0.675
AC XY:
489818
AN XY:
725538
show subpopulations
African (AFR)
AF:
0.630
AC:
21068
AN:
33432
American (AMR)
AF:
0.790
AC:
35289
AN:
44684
Ashkenazi Jewish (ASJ)
AF:
0.614
AC:
16042
AN:
26106
East Asian (EAS)
AF:
0.782
AC:
30962
AN:
39616
South Asian (SAS)
AF:
0.634
AC:
54648
AN:
86194
European-Finnish (FIN)
AF:
0.675
AC:
36021
AN:
53400
Middle Eastern (MID)
AF:
0.640
AC:
3685
AN:
5756
European-Non Finnish (NFE)
AF:
0.676
AC:
750196
AN:
1110050
Other (OTH)
AF:
0.671
AC:
40473
AN:
60276
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
17828
35655
53483
71310
89138
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
19392
38784
58176
77568
96960
<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:
0.670
AC:
101794
AN:
151882
Hom.:
34332
Cov.:
31
AF XY:
0.669
AC XY:
49628
AN XY:
74222
show subpopulations
African (AFR)
AF:
0.637
AC:
26370
AN:
41398
American (AMR)
AF:
0.728
AC:
11119
AN:
15270
Ashkenazi Jewish (ASJ)
AF:
0.628
AC:
2180
AN:
3472
East Asian (EAS)
AF:
0.795
AC:
4098
AN:
5152
South Asian (SAS)
AF:
0.657
AC:
3157
AN:
4806
European-Finnish (FIN)
AF:
0.663
AC:
6967
AN:
10514
Middle Eastern (MID)
AF:
0.605
AC:
178
AN:
294
European-Non Finnish (NFE)
AF:
0.672
AC:
45701
AN:
67960
Other (OTH)
AF:
0.683
AC:
1437
AN:
2104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
1719
3439
5158
6878
8597
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
818
1636
2454
3272
4090
<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:
0.663
Hom.:
10887
Bravo
AF:
0.677
TwinsUK
AF:
0.681
AC:
2526
ALSPAC
AF:
0.661
AC:
2549
ESP6500AA
AF:
0.629
AC:
2772
ESP6500EA
AF:
0.669
AC:
5752
ExAC
AF:
0.685
AC:
83160
Asia WGS
AF:
0.717
AC:
2494
AN:
3478
EpiCase
AF:
0.663
EpiControl
AF:
0.661

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.60
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
0.0070
DANN
Benign
0.62
DEOGEN2
Benign
0.15
T
Eigen
Benign
-1.9
Eigen_PC
Benign
-1.9
FATHMM_MKL
Benign
0.027
N
LIST_S2
Benign
0.11
T
MetaRNN
Benign
0.0000011
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.37
N
PhyloP100
-3.1
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.89
N
REVEL
Benign
0.26
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0
B
Vest4
0.027
MPC
0.23
ClinPred
0.0020
T
GERP RS
-3.9
Varity_R
0.087
gMVP
0.35
Mutation Taster
=99/1
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs5516; hg19: chr19-51323473; COSMIC: COSV56826320; COSMIC: COSV56826320; API