19-51006658-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012315.2(KLK9):​c.266G>A​(p.Arg89Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KLK9
NM_012315.2 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.631
Variant links:
Genes affected
KLK9 (HGNC:6370): (kallikrein related peptidase 9) The protein encoded by this gene is a kallikrein-related serine protease. This gene is activated by steroid hormones in a human breast cancer cell line, making it a good marker for cancer detection. The encoded protein is found primarily in the cytoplasm.[provided by RefSeq, Oct 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18465137).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KLK9NM_012315.2 linkc.266G>A p.Arg89Gln missense_variant Exon 3 of 5 ENST00000594211.2 NP_036447.1 Q9UKQ9-1Q2XQG6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KLK9ENST00000594211.2 linkc.266G>A p.Arg89Gln missense_variant Exon 3 of 5 1 NM_012315.2 ENSP00000469417.1 Q9UKQ9-1
ENSG00000269741ENST00000250366.6 linkn.266G>A non_coding_transcript_exon_variant Exon 3 of 7 2 ENSP00000250366.5
KLK9ENST00000544410.1 linkn.109G>A non_coding_transcript_exon_variant Exon 2 of 4 2 ENSP00000443289.1 Q9UKQ9-2
ENSG00000267879ENST00000594512.1 linkn.430-5365C>T intron_variant Intron 3 of 3 4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151876
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000948
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000799
AC:
2
AN:
250330
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135260
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000927
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460558
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
726540
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151876
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74178
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000948
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 09, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.266G>A (p.R89Q) alteration is located in exon 3 (coding exon 3) of the KLK9 gene. This alteration results from a G to A substitution at nucleotide position 266, causing the arginine (R) at amino acid position 89 to be replaced by a glutamine (Q). 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
0.13
BayesDel_addAF
Benign
-0.021
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.23
T
Eigen
Benign
-0.61
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.013
N
M_CAP
Benign
0.037
D
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.46
N
PrimateAI
Benign
0.34
T
Sift4G
Benign
0.61
T
Polyphen
0.90
P
Vest4
0.28
MutPred
0.31
Loss of sheet (P = 0.1398);
MVP
0.77
ClinPred
0.38
T
GERP RS
1.7
Varity_R
0.039
gMVP
0.49

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

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

Other links and lift over

dbSNP: rs766128169; hg19: chr19-51509914; API