19-50967314-C-T

Variant names:

• chr19-50967314-C-T
• rs913095973
• NM_002774.4:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002774.4(KLK6):​c.52G>A​(p.Glu18Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,368 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KLK6 NM_002774.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13060537).

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.52G>A	p.Glu18Lys	missense	Exon 4 of 7	NP_002765.1	Q92876-1
	KLK6	NM_001012964.3		c.52G>A	p.Glu18Lys	missense	Exon 3 of 6	NP_001012982.1	Q92876-1
	KLK6	NM_001012965.3		c.-270G>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.52G>A	p.Glu18Lys	missense	Exon 4 of 7	ENSP00000309148.1	Q92876-1
	KLK6	ENST00000376851.7	TSL:1	c.52G>A	p.Glu18Lys	missense	Exon 3 of 6	ENSP00000366047.2	Q92876-1
	KLK6	ENST00000594641.1	TSL:1	c.52G>A	p.Glu18Lys	missense	Exon 2 of 5	ENSP00000470482.1	Q92876-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454368 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722492

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.0000226 AC: 1 AN: 44178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 85562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107090

Other (OTH) AF: 0.00 AC: 0 AN: 60048

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.14
BayesDel_addAF	Benign	0.0059	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.34
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.19	T
Sift4G	Uncertain	0.050	T
Polyphen		0.032	B
Vest4		0.19
MutPred		0.49		Gain of ubiquitination at E18 (P = 0.0258)
MVP		0.96
MPC		0.51
ClinPred		0.37	T
GERP RS		2.1
Varity_R		0.12
gMVP		0.49
Mutation Taster		=296/4	polymorphism

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

Other links and lift over

dbSNP: rs913095973; hg19: chr19-51470570; COSMIC: COSV100037833; COSMIC: COSV100037833;