Variant 19-50963401-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_002774.4(KLK6):c.346G>A(p.Ala116Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KLK6
NM_002774.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25304365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK6	NM_002774.4 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	5/7	ENST00000310157.7	NP_002765.1	Q92876-1A0A024R4J8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK6	ENST00000310157.7 linkuse as main transcript	c.346G>A	p.Ala116Thr	missense_variant	5/7	1	NM_002774.4	ENSP00000309148.1		Q92876-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135882

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:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 02, 2022

The c.346G>A (p.A116T) alteration is located in exon 4 (coding exon 3) of the KLK6 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the alanine (A) at amino acid position 116 to be replaced by a threonine (T). 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

0.18

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

D;D;.;D

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.64

.;.;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Uncertain

0.020

MutationAssessor

Uncertain

2.4

M;M;.;M

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.8

D;D;N;.

REVEL

Benign

0.27

Sift

Benign

0.040

D;D;D;.

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.32

B;B;B;B

Vest4

0.22

MutPred

0.65

Gain of phosphorylation at A116 (P = 0.0276);Gain of phosphorylation at A116 (P = 0.0276);.;Gain of phosphorylation at A116 (P = 0.0276);

MVP

0.93

MPC

0.21

ClinPred

0.18

GERP RS

1.0

Varity_R

0.41

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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