chr19-50963515-G-A

Position:

• chr19-50963515-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001012965.3(KLK6):​c.-90C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 1,614,038 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (217 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (205 hom.)
• Consequence: KLK6 NM_001012965.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0680

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019099414).
• BP6: Variant 19-50963515-G-A is Benign according to our data. Variant chr19-50963515-G-A is described in ClinVar as [Benign]. Clinvar id is 781517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK6	NM_002774.4	c.232C>T	p.Arg78Trp	missense_variant	5/7	ENST00000310157.7	NP_002765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK6	ENST00000310157.7	c.232C>T	p.Arg78Trp	missense_variant	5/7	1	NM_002774.4	ENSP00000309148.1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4465 AN: 152048 Hom.: 217 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00783 AC: 1969 AN: 251382 Hom.: 105 AF XY: 0.00548 AC XY: 744 AN XY: 135876

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00303 AC: 4428 AN: 1461872 Hom.: 205 Cov.: 32 AF XY: 0.00259 AC XY: 1885 AN XY: 727240

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.00601

GnomAD4 genome AF: 0.0294 AC: 4475 AN: 152166 Hom.: 217 Cov.: 32 AF XY: 0.0281 AC XY: 2093 AN XY: 74398

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00532 Hom.: 53

Bravo AF: 0.0349

ESP6500AA AF: 0.112 AC: 492

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00969 AC: 1176

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;D
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.46	.;.;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.6	D;D;.
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D;D;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.0020	B;B;B
Vest4		0.26
MVP		0.90
MPC		0.55
ClinPred		0.048	T
GERP RS		1.1
Varity_R		0.37
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs61469141; hg19: chr19-51466771;