19-50949006-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012427.5(KLK5):​c.445G>A​(p.Gly149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

KLK5
NM_012427.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.186
Variant links:
Genes affected
KLK5 (HGNC:6366): (kallikrein related peptidase 5) 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. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLK5NM_012427.5 linkc.445G>A p.Gly149Ser missense_variant Exon 4 of 6 ENST00000336334.8 NP_036559.1 Q9Y337

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLK5ENST00000336334.8 linkc.445G>A p.Gly149Ser missense_variant Exon 4 of 6 1 NM_012427.5 ENSP00000337733.2 Q9Y337

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151876
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000103
AC:
26
AN:
251458
Hom.:
0
AF XY:
0.0000883
AC XY:
12
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000752
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000205
AC:
30
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151876
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
74148
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000656
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000494
AC:
6

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 14, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.445G>A (p.G149S) alteration is located in exon 4 (coding exon 3) of the KLK5 gene. This alteration results from a G to A substitution at nucleotide position 445, causing the glycine (G) at amino acid position 149 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
5.6
DANN
Benign
0.48
DEOGEN2
Benign
0.24
T;T;T;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.044
.;.;T;T
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.043
T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
-0.72
N;N;N;.
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.86
N;N;.;.
REVEL
Benign
0.20
Sift
Benign
0.87
T;T;.;.
Sift4G
Benign
0.90
T;T;T;.
Polyphen
0.029
B;B;B;.
Vest4
0.087
MutPred
0.31
Gain of disorder (P = 0.0695);Gain of disorder (P = 0.0695);Gain of disorder (P = 0.0695);Gain of disorder (P = 0.0695);
MVP
0.48
MPC
0.099
ClinPred
0.019
T
GERP RS
-1.7
Varity_R
0.16
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.23
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.23
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs761551466; hg19: chr19-51452262; API