19-50996112-T-C

Position:

• chr19-50996112-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007196.4(KLK8):​c.730A>G​(p.Asn244Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLK8 NM_007196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK8	NM_007196.4	c.730A>G	p.Asn244Asp	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.730A>G	p.Asn244Asp	missense_variant	6/6		NM_007196.4	ENSP00000512260.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Mar 24, 2023

The c.865A>G (p.N289D) alteration is located in exon 6 (coding exon 5) of the KLK8 gene. This alteration results from a A to G substitution at nucleotide position 865, causing the asparagine (N) at amino acid position 289 to be replaced by an aspartic acid (D). 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	0.18
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;.;D;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.57	.;.;N;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D;.;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.16	T;.;.;T
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.92	P;.;B;B
Vest4		0.46
MutPred		0.61		.;.;Loss of MoRF binding (P = 0.0608);.;
MVP		0.87
MPC		0.81
ClinPred		0.88	D
GERP RS		4.7
Varity_R		0.53
gMVP		0.74

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: chr19-51499368;