Genetic Variant KLK6:p.Val89Leu (chr19-50963482-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_002774.4(KLK6):c.265G>C(p.Val89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KLK6
NM_002774.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.879

Variant links:

Genes affected

KLK6 (HGNC:6367): (kallikrein related peptidase 6) This gene encodes a member of the kallikrein subfamily of the peptidase S1 family of serine proteases. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The encoded preproprotein is proteolytically processed to generate the mature protease. Expression of this protease is regulated by steroid hormones and may be elevated in multiple human cancers and in serum from psoriasis patients. The encoded protease may participate in the cleavage of amyloid precursor protein and alpha-synuclein, thus implicating this protease in Alzheimer's and Parkinson's disease, respectively. This gene is located in a gene cluster on chromosome 19. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

KLK6 links:

ENSG00000269495 (HGNC:):

ENSG00000269495 links:

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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
KLK6	NM_002774.4 link	c.265G>C	p.Val89Leu	missense_variant	Exon 5 of 7	ENST00000310157.7	NP_002765.1	Q92876-1A0A024R4J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK6	ENST00000310157.7 link	c.265G>C	p.Val89Leu	missense_variant	Exon 5 of 7	1	NM_002774.4	ENSP00000309148.1		Q92876-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>C (p.V89L) alteration is located in exon 4 (coding exon 3) of the KLK6 gene. This alteration results from a G to C substitution at nucleotide position 265, causing the valine (V) at amino acid position 89 to be replaced by a leucine (L). 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

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;D;D

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.73

.;.;T

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;N;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0070

D;D;.

Sift4G

Uncertain

0.033

D;D;D

Polyphen

0.16

B;B;B

Vest4

0.40

MutPred

0.65

Gain of disorder (P = 0.2019);Gain of disorder (P = 0.2019);Gain of disorder (P = 0.2019);

MVP

0.94

MPC

0.58

ClinPred

0.64

GERP RS

4.7

Varity_R

0.56

gMVP

0.59

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over