dbSNP rs2292186: KLK3:c.46+137C>T (chr19-50855138-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001648.2(KLK3):c.46+137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 797,496 control chromosomes in the GnomAD database, including 29,151 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 4719 hom., cov: 28)

Exomes 𝑓: 0.27 ( 24432 hom. )

Consequence

KLK3
NM_001648.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.446

Publications

7 publications found

Variant links:

Genes affected

KLK3 (HGNC:6364): (kallikrein related peptidase 3) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

KLK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001648.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLK3	NM_001648.2	MANE Select	c.46+137C>T	intron	N/A	NP_001639.1	Q546G3
KLK3	NM_001030047.1		c.46+137C>T	intron	N/A	NP_001025218.1	P07288-2
KLK3	NM_001030048.1		c.46+137C>T	intron	N/A	NP_001025219.1	P07288-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLK3	ENST00000326003.7	TSL:1 MANE Select	c.46+137C>T	intron	N/A	ENSP00000314151.1	P07288-1
KLK3	ENST00000360617.7	TSL:1	c.46+137C>T	intron	N/A	ENSP00000353829.2	P07288-2
KLK3	ENST00000593997.5	TSL:1	c.46+137C>T	intron	N/A	ENSP00000472907.1	P07288-5

Frequencies

GnomAD3 genomes

AF:

0.228

AC:

34451

AN:

151134

Hom.:

4713

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0878

Gnomad AMI

AF:

0.254

Gnomad AMR

AF:

0.326

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.351

Gnomad SAS

AF:

0.165

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.269

Gnomad OTH

AF:

0.215

GnomAD2 exomes

AF:

0.280

AC:

30990

AN:

110526

AF XY:

0.272

show subpopulations

Gnomad AFR exome

AF:

0.0853

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.355

Gnomad FIN exome

AF:

0.338

Gnomad NFE exome

AF:

0.268

Gnomad OTH exome

AF:

0.257

GnomAD4 exome

AF:

0.267

AC:

172389

AN:

646246

Hom.:

24432

Cov.:

AF XY:

0.262

AC XY:

88860

AN XY:

339646

show subpopulations

African (AFR)

AF:

0.0858

AC:

1486

AN:

17318

American (AMR)

AF:

0.398

AC:

12286

AN:

30904

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

4037

AN:

17732

East Asian (EAS)

AF:

0.347

AC:

11278

AN:

32518

South Asian (SAS)

AF:

0.172

AC:

10141

AN:

58842

European-Finnish (FIN)

AF:

0.341

AC:

12265

AN:

35984

Middle Eastern (MID)

AF:

0.146

AC:

470

AN:

3216

European-Non Finnish (NFE)

AF:

0.269

AC:

112254

AN:

416704

Other (OTH)

AF:

0.247

AC:

8172

AN:

33028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

6250

12499

18749

24998

31248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1858

3716

5574

7432

9290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.228

AC:

34469

AN:

151250

Hom.:

4719

Cov.:

AF XY:

0.230

AC XY:

16960

AN XY:

73808

show subpopulations

African (AFR)

AF:

0.0877

AC:

3623

AN:

41328

American (AMR)

AF:

0.326

AC:

4949

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

801

AN:

3466

East Asian (EAS)

AF:

0.350

AC:

1776

AN:

5068

South Asian (SAS)

AF:

0.166

AC:

791

AN:

4776

European-Finnish (FIN)

AF:

0.344

AC:

3590

AN:

10428

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.269

AC:

18191

AN:

67702

Other (OTH)

AF:

0.222

AC:

468

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1185

2371

3556

4742

5927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.236

Hom.:

1378

Bravo

AF:

0.222

Asia WGS

AF:

0.262

AC:

910

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

(source)

DANN

Benign

0.32

PhyloP100

0.45

PromoterAI

-0.0030

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over