19-50967290-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002774.4(KLK6):​c.76G>A​(p.Gly26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KLK6 NM_002774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0420
• Publications: 6 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.106910944).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002774.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK6	NM_002774.4	MANE Select	c.76G>A	p.Gly26Arg	missense	Exon 4 of 7	NP_002765.1	Q92876-1
	KLK6	NM_001012964.3		c.76G>A	p.Gly26Arg	missense	Exon 3 of 6	NP_001012982.1	Q92876-1
	KLK6	NM_001012965.3		c.-246G>A		5_prime_UTR	Exon 2 of 5	NP_001012983.1	Q92876-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK6	ENST00000310157.7	TSL:1 MANE Select	c.76G>A	p.Gly26Arg	missense	Exon 4 of 7	ENSP00000309148.1	Q92876-1
	KLK6	ENST00000376851.7	TSL:1	c.76G>A	p.Gly26Arg	missense	Exon 3 of 6	ENSP00000366047.2	Q92876-1
	KLK6	ENST00000594641.1	TSL:1	c.76G>A	p.Gly26Arg	missense	Exon 2 of 5	ENSP00000470482.1	Q92876-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000560 AC: 14 AN: 250206 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461002 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000201 AC: 9 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111432

Other (OTH) AF: 0.0000497 AC: 3 AN: 60354

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74216

African (AFR) AF: 0.0000242 AC: 1 AN: 41356

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-0.41	N
PhyloP100		-0.042
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.25	N
REVEL	Benign	0.26
Sift	Benign	0.31	T
Sift4G	Benign	0.35	T
Polyphen		0.15	B
Vest4		0.34
MutPred		0.51		Loss of ubiquitination at K21 (P = 0.0435)
MVP		0.92
MPC		0.80
ClinPred		0.077	T
GERP RS		0.69
Varity_R		0.30
gMVP		0.78
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200733164; hg19: chr19-51470546; COSMIC: COSV59565508; COSMIC: COSV59565508;