19-51081568-C-T

Variant names:

• chr19-51081568-C-T
• rs781139205
• NM_001369775.2:c.176G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001369775.2(KLK14):​c.176G>A​(p.Gly59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,392,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G59V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: KLK14 NM_001369775.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034576684).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369775.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK14	NM_001369775.2	MANE Select	c.176G>A	p.Gly59Asp	missense	Exon 3 of 6	NP_001356704.1	A0A1R3UHJ7
	KLK14	NM_001311182.2		c.176G>A	p.Gly59Asp	missense	Exon 4 of 8	NP_001298111.2	A0A1R3UHJ7
	KLK14	NM_022046.6		c.176G>A	p.Gly59Asp	missense	Exon 4 of 7	NP_071329.3	A0A1R3UHJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK14	ENST00000650543.2	MANE Select	c.176G>A	p.Gly59Asp	missense	Exon 3 of 6	ENSP00000497141.1	A0A1R3UHJ7
	KLK14	ENST00000156499.7	TSL:1	c.176G>A	p.Gly59Asp	missense	Exon 4 of 8	ENSP00000156499.3	A0A1R3UHJ7
	KLK14	ENST00000391802.1	TSL:5	c.224G>A	p.Gly75Asp	missense	Exon 4 of 7	ENSP00000375678.1	Q9P0G3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1392202 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685902

African (AFR) AF: 0.00 AC: 0 AN: 31508

American (AMR) AF: 0.00 AC: 0 AN: 34884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24658

East Asian (EAS) AF: 0.00 AC: 0 AN: 35678

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1074770

Other (OTH) AF: 0.00 AC: 0 AN: 57642

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.0
DANN	Benign	0.27
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.010	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.77	N
PhyloP100		-0.10
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.44		Gain of solvent accessibility (P = 0.0281)
MVP		0.17
MPC		0.19
ClinPred		0.042	T
GERP RS		-1.1
Varity_R		0.041
gMVP		0.57
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs781139205; hg19: chr19-51584825;