19-51078898-C-T

Variant names:

• chr19-51078898-C-T
• NM_001369775.2:c.520G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001369775.2(KLK14):​c.520G>A​(p.Val174Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLK14 NM_001369775.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.78

Genes affected

KLK14 (HGNC:6362): (kallikrein related peptidase 14) This gene encodes a member of the kallikrein subfamily of serine proteases that have diverse physiological functions such as regulation of blood pressure and desquamation. The altered expression of this gene is implicated in the progression of different cancers including breast and prostate tumors. The encoded protein is a precursor that is proteolytically processed to generate the functional enzyme. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37690336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK14	NM_001369775.2	c.520G>A	p.Val174Met	missense_variant	Exon 5 of 6	ENST00000650543.2	NP_001356704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK14	ENST00000650543.2	c.520G>A	p.Val174Met	missense_variant	Exon 5 of 6		NM_001369775.2	ENSP00000497141.1
KLK14	ENST00000156499.7	c.520G>A	p.Val174Met	missense_variant	Exon 6 of 8	1		ENSP00000156499.3
KLK14	ENST00000391802.1	c.568G>A	p.Val190Met	missense_variant	Exon 6 of 7	5		ENSP00000375678.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568G>A (p.V190M) alteration is located in exon 6 (coding exon 5) of the KLK14 gene. This alteration results from a G to A substitution at nucleotide position 568, causing the valine (V) at amino acid position 190 to be replaced by a methionine (M). 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	0.19
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	.;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.27	.;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	2.0	.;M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.48	.;N;.
REVEL	Uncertain	0.33
Sift	Benign	0.044	.;D;.
Sift4G	Uncertain	0.055	.;T;.
Polyphen		0.75	.;P;.
Vest4		0.27
MutPred		0.39		.;Gain of ubiquitination at K193 (P = 0.0741);.;
MVP		0.86
MPC		0.46
ClinPred		0.38	T
GERP RS		-3.3
Varity_R		0.066
gMVP		0.40

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51582155;