chr19-50996093-T-G

Position:

• chr19-50996093-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007196.4(KLK8):​c.749A>C​(p.Asp250Ala) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLK8 NM_007196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.445

Genes affected

KLK8 (HGNC:6369): (kallikrein related peptidase 8) 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 tandem in a gene cluster on chromosome 19. The encoded protein may be involved in proteolytic cascade in the skin and may serve as a biomarker for ovarian cancer. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

KLK8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35831144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK8	NM_007196.4	c.749A>C	p.Asp250Ala	missense_variant	6/6	ENST00000695909.1	NP_009127.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK8	ENST00000695909.1	c.749A>C	p.Asp250Ala	missense_variant	6/6		NM_007196.4	ENSP00000512260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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 01, 2024

The c.884A>C (p.D295A) alteration is located in exon 6 (coding exon 5) of the KLK8 gene. This alteration results from a A to C substitution at nucleotide position 884, causing the aspartic acid (D) at amino acid position 295 to be replaced by an alanine (A). 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	0.15
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	.;.;D;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.12	T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.1	.;.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.6	D;.;.;D
REVEL	Uncertain	0.33
Sift	Benign	0.077	T;.;.;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.57	P;.;B;B
Vest4		0.26
MutPred		0.54		.;.;Gain of catalytic residue at D250 (P = 0.0372);.;
MVP		0.82
MPC		0.46
ClinPred		0.26	T
GERP RS		3.6
Varity_R		0.45
gMVP		0.87

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

LitVar

Other links and lift over

dbSNP: rs777146021; hg19: chr19-51499349;