19-50876681-T-C

Position:

• chr19-50876681-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005551.5(KLK2):​c.416T>C​(p.Leu139Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLK2 NM_005551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.954

Genes affected

KLK2 (HGNC:6363): (kallikrein related peptidase 2) This gene encodes a member of the grandular kallikrein protein family. Kallikreins are a subgroup of serine proteases that are clustered on chromosome 19. Members of this family are involved in a diverse array of biological functions. The protein encoded by this gene is a highly active trypsin-like serine protease that selectively cleaves at arginine residues. This protein is primarily expressed in prostatic tissue and is responsible for cleaving pro-prostate-specific antigen into its enzymatically active form. This gene is highly expressed in prostate tumor cells and may be a prognostic maker for prostate cancer risk. Alternate splicing results in both coding and non-coding transcript variants. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK2	NM_005551.5	c.416T>C	p.Leu139Pro	missense_variant	3/5	ENST00000325321.8	NP_005542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK2	ENST00000325321.8	c.416T>C	p.Leu139Pro	missense_variant	3/5	1	NM_005551.5	ENSP00000313581.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

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

Oct 12, 2024

The c.416T>C (p.L139P) alteration is located in exon 3 (coding exon 3) of the KLK2 gene. This alteration results from a T to C substitution at nucleotide position 416, causing the leucine (L) at amino acid position 139 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	0.72
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.7	L;.;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.0	D;D;D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;D;D;.
Sift4G	Benign	0.064	T;T;D;D
Polyphen		0.80	P;.;P;.
Vest4		0.40
MutPred		0.91		Loss of catalytic residue at L139 (P = 0.0391);.;Loss of catalytic residue at L139 (P = 0.0391);.;
MVP		0.82
MPC		0.42
ClinPred		0.93	D
GERP RS		-2.1
Varity_R		0.71
gMVP		0.72

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: chr19-51379937;