Genetic Variant NM_002774.4:c.302C>T (chr19-50963445-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002774.4(KLK6):c.302C>T(p.Ala101Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A101T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLK6
NM_002774.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.189

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13308987).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002774.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK6	NM_002774.4	MANE Select	c.302C>T	p.Ala101Val	missense	Exon 5 of 7	NP_002765.1	Q92876-1
KLK6	NM_001012964.3		c.302C>T	p.Ala101Val	missense	Exon 4 of 6	NP_001012982.1	Q92876-1
KLK6	NM_001012965.3		c.-20C>T		5_prime_UTR	Exon 3 of 5	NP_001012983.1	Q92876-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK6	ENST00000310157.7	TSL:1 MANE Select	c.302C>T	p.Ala101Val	missense	Exon 5 of 7	ENSP00000309148.1	Q92876-1
KLK6	ENST00000376851.7	TSL:1	c.302C>T	p.Ala101Val	missense	Exon 4 of 6	ENSP00000366047.2	Q92876-1
KLK6	ENST00000594641.1	TSL:1	c.302C>T	p.Ala101Val	missense	Exon 3 of 5	ENSP00000470482.1	Q92876-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.091

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.14

PhyloP100

-0.19

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Benign

0.037

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.25

MutPred

0.34

Loss of disorder (P = 0.0774)

MVP

0.92

MPC

0.24

ClinPred

0.063

GERP RS

1.2

Varity_R

0.15

gMVP

0.32

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over