19-50967290-C-G

Variant names:

• chr19-50967290-C-G
• rs200733164
• NM_002774.4:c.76G>C

Variant summary

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

The NM_002774.4(KLK6):​c.76G>C​(p.Gly26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLK6 NM_002774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0420

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]

LOC105372442 (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=0.18899462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK6	NM_002774.4	c.76G>C	p.Gly26Arg	missense_variant	Exon 4 of 7	ENST00000310157.7	NP_002765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK6	ENST00000310157.7	c.76G>C	p.Gly26Arg	missense_variant	Exon 4 of 7	1	NM_002774.4	ENSP00000309148.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250206 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461002 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726752

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>C (p.G26R) alteration is located in exon 3 (coding exon 2) of the KLK6 gene. This alteration results from a G to C substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 to be replaced by an arginine (R). 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	Benign	-0.11	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.8
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.71	.;.;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.41	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.25	N;N;.
REVEL	Benign	0.28
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.35	T;T;T
Polyphen		0.076	B;B;B
Vest4		0.34
MutPred		0.51		Loss of ubiquitination at K21 (P = 0.0435);Loss of ubiquitination at K21 (P = 0.0435);Loss of ubiquitination at K21 (P = 0.0435);
MVP		0.92
MPC		0.80
ClinPred		0.25	T
GERP RS		0.69
Varity_R		0.30
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200733164; hg19: chr19-51470546;