19-50943714-C-A

Position:

• chr19-50943714-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012427.5(KLK5):​c.799G>T​(p.Ala267Ser) variant causes a missense change involving the alteration of a 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: 31)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.82

Genes affected

KLK5 (HGNC:6366): (kallikrein related peptidase 5) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

KLK5 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK5	NM_012427.5	c.799G>T	p.Ala267Ser	missense_variant	6/6	ENST00000336334.8	NP_036559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK5	ENST00000336334.8	c.799G>T	p.Ala267Ser	missense_variant	6/6	1	NM_012427.5	ENSP00000337733.2
KLK5	ENST00000391809.6	c.799G>T	p.Ala267Ser	missense_variant	7/7	1		ENSP00000375685.1
KLK5	ENST00000593428.5	c.799G>T	p.Ala267Ser	missense_variant	6/6	1		ENSP00000471966.1
KLK5	ENST00000595585.1	n.895G>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Dec 28, 2022

The c.799G>T (p.A267S) alteration is located in exon 6 (coding exon 5) of the KLK5 gene. This alteration results from a G to T substitution at nucleotide position 799, causing the alanine (A) at amino acid position 267 to be replaced by a serine (S). 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	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T;T
Eigen	Benign	0.053
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	.;.;T
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Benign	1.1	L;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N;N;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.013	D;D;.
Sift4G	Benign	0.086	T;T;T
Polyphen		0.66	P;P;P
Vest4		0.25
MutPred		0.81		Gain of disorder (P = 0.0514);Gain of disorder (P = 0.0514);Gain of disorder (P = 0.0514);
MVP		0.98
MPC		0.24
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61729816; hg19: chr19-51446970;