chr19-51079484-C-G

Position:

• chr19-51079484-C-G

Variant summary

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

The NM_001369775.2(KLK14):​c.431G>C​(p.Arg144Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: -2.73

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK14	NM_001369775.2	c.431G>C	p.Arg144Pro	missense_variant	4/6	ENST00000650543.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK14	ENST00000650543.2	c.431G>C	p.Arg144Pro	missense_variant	4/6		NM_001369775.2	P1
KLK14	ENST00000156499.7	c.431G>C	p.Arg144Pro	missense_variant	5/8	1		P1
KLK14	ENST00000391802.1	c.479G>C	p.Arg160Pro	missense_variant	5/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000992 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2021

The c.479G>C (p.R160P) alteration is located in exon 5 (coding exon 4) of the KLK14 gene. This alteration results from a G to C substitution at nucleotide position 479, causing the arginine (R) at amino acid position 160 to be replaced by a proline (P). 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	0.83
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.069	N
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;N;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.020	D;D;.
Polyphen		0.99	.;D;.
Vest4		0.34
MutPred		0.65		.;Gain of glycosylation at S158 (P = 0.0462);.;
MVP		0.72
MPC		0.71
ClinPred		0.56	D
GERP RS		-8.2
Varity_R		0.79
gMVP		0.90

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

Other links and lift over

dbSNP: rs184705974; hg19: chr19-51582741;