19-50959185-T-A

Position:

• chr19-50959185-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002774.4(KLK6):​c.714A>T​(p.Gln238His) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLK6 NM_002774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.110

Genes affected

KLK6 (HGNC:6367): (kallikrein related peptidase 6) This gene encodes a member of the kallikrein subfamily of the peptidase S1 family of serine proteases. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The encoded preproprotein is proteolytically processed to generate the mature protease. Expression of this protease is regulated by steroid hormones and may be elevated in multiple human cancers and in serum from psoriasis patients. The encoded protease may participate in the cleavage of amyloid precursor protein and alpha-synuclein, thus implicating this protease in Alzheimer's and Parkinson's disease, respectively. This gene is located in a gene cluster on chromosome 19. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ENSG00000269495 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09085566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK6	NM_002774.4	c.714A>T	p.Gln238His	missense_variant	7/7	ENST00000310157.7	NP_002765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK6	ENST00000310157.7	c.714A>T	p.Gln238His	missense_variant	7/7	1	NM_002774.4	ENSP00000309148.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

Feb 06, 2023

The c.714A>T (p.Q238H) alteration is located in exon 6 (coding exon 5) of the KLK6 gene. This alteration results from a A to T substitution at nucleotide position 714, causing the glutamine (Q) at amino acid position 238 to be replaced by a histidine (H). 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	0.26
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.25
CADD	Benign	9.7
DANN	Benign	0.50
DEOGEN2	Uncertain	0.58	D;D;.;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.18	.;.;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.091	T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	L;L;.;L
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.20	T;T;T;.
Sift4G	Uncertain	0.017	D;D;T;D
Polyphen		0.0	B;B;B;B
Vest4		0.14
MutPred		0.33		Loss of stability (P = 0.1074);Loss of stability (P = 0.1074);.;Loss of stability (P = 0.1074);
MVP		0.79
MPC		0.20
ClinPred		0.038	T
GERP RS		-2.2
Varity_R		0.35
gMVP		0.42

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: chr19-51462441;