rs112710289

Variant names:

• chr19-51079680-T-C
• rs112710289
• NM_001369775.2:c.235A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001369775.2(KLK14):​c.235A>G​(p.Lys79Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000382 in 1,569,662 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLK14 NM_001369775.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.506
• Publications: 0 publications found

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

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=0.20428672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK14	NM_001369775.2	c.235A>G	p.Lys79Glu	missense_variant	Exon 4 of 6	ENST00000650543.2	NP_001356704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK14	ENST00000650543.2	c.235A>G	p.Lys79Glu	missense_variant	Exon 4 of 6		NM_001369775.2	ENSP00000497141.1
KLK14	ENST00000156499.7	c.235A>G	p.Lys79Glu	missense_variant	Exon 5 of 8	1		ENSP00000156499.3
KLK14	ENST00000391802.1	c.283A>G	p.Lys95Glu	missense_variant	Exon 5 of 7	5		ENSP00000375678.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417382 Hom.: 0 Cov.: 31 AF XY: 0.00000285 AC XY: 2 AN XY: 701534

African (AFR) AF: 0.00 AC: 0 AN: 32450

American (AMR) AF: 0.00 AC: 0 AN: 37922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25362

East Asian (EAS) AF: 0.00 AC: 0 AN: 37166

South Asian (SAS) AF: 0.00 AC: 0 AN: 81648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089336

Other (OTH) AF: 0.00 AC: 0 AN: 58750

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74470

African (AFR) AF: 0.0000481 AC: 2 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283A>G (p.K95E) alteration is located in exon 5 (coding exon 4) of the KLK14 gene. This alteration results from a A to G substitution at nucleotide position 283, causing the lysine (K) at amino acid position 95 to be replaced by a glutamic acid (E). 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	0.62
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.57
DEOGEN2	Benign	0.037	.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.0089
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.48	.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	-0.88	.;N;.
PhyloP100		0.51
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.16	.;N;.
REVEL	Uncertain	0.34
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		1.0	.;D;.
Vest4		0.16
MutPred		0.60		.;Loss of MoRF binding (P = 0.002);.;
MVP		0.72
MPC		0.71
ClinPred		0.37	T
GERP RS		5.2
Varity_R		0.22
gMVP		0.62
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs112710289; hg19: chr19-51582937;