Genetic Variant NM_001648.2:c.46+214C>G (chr19-50855215-C-G) – 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+214C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 568,230 control chromosomes in the GnomAD database, including 59,414 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 0.46 ( 16962 hom., cov: 29)

Exomes 𝑓: 0.44 ( 42452 hom. )

Consequence

KLK3
NM_001648.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.316

Publications

6 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 (AFR) allele frequency at 95% confidence interval = 0.521 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+214C>G	intron	N/A	NP_001639.1	Q546G3
KLK3	NM_001030047.1		c.46+214C>G	intron	N/A	NP_001025218.1	P07288-2
KLK3	NM_001030048.1		c.46+214C>G	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+214C>G	intron	N/A	ENSP00000314151.1	P07288-1
KLK3	ENST00000360617.7	TSL:1	c.46+214C>G	intron	N/A	ENSP00000353829.2	P07288-2
KLK3	ENST00000593997.5	TSL:1	c.46+214C>G	intron	N/A	ENSP00000472907.1	P07288-5

Frequencies

GnomAD3 genomes

AF:

0.464

AC:

70424

AN:

151668

Hom.:

16955

Cov.:

show subpopulations

Gnomad AFR

AF:

0.527

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.355

Gnomad ASJ

AF:

0.428

Gnomad EAS

AF:

0.161

Gnomad SAS

AF:

0.386

Gnomad FIN

AF:

0.503

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.478

Gnomad OTH

AF:

0.449

GnomAD2 exomes

AF:

0.388

AC:

17806

AN:

45858

AF XY:

0.388

show subpopulations

Gnomad AFR exome

AF:

0.515

Gnomad AMR exome

AF:

0.296

Gnomad ASJ exome

AF:

0.391

Gnomad EAS exome

AF:

0.153

Gnomad FIN exome

AF:

0.515

Gnomad NFE exome

AF:

0.478

Gnomad OTH exome

AF:

0.418

GnomAD4 exome

AF:

0.440

AC:

183280

AN:

416446

Hom.:

42452

Cov.:

AF XY:

0.439

AC XY:

96083

AN XY:

218950

show subpopulations

African (AFR)

AF:

0.521

AC:

5916

AN:

11346

American (AMR)

AF:

0.295

AC:

5171

AN:

17504

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

5512

AN:

12758

East Asian (EAS)

AF:

0.188

AC:

5430

AN:

28928

South Asian (SAS)

AF:

0.399

AC:

15982

AN:

40056

European-Finnish (FIN)

AF:

0.501

AC:

14355

AN:

28636

Middle Eastern (MID)

AF:

0.463

AC:

850

AN:

1836

European-Non Finnish (NFE)

AF:

0.475

AC:

119223

AN:

251102

Other (OTH)

AF:

0.446

AC:

10841

AN:

24280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

4543

9087

13630

18174

22717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.464

AC:

70459

AN:

151784

Hom.:

16962

Cov.:

AF XY:

0.461

AC XY:

34227

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.527

AC:

21770

AN:

41344

American (AMR)

AF:

0.354

AC:

5398

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

1485

AN:

3468

East Asian (EAS)

AF:

0.162

AC:

837

AN:

5154

South Asian (SAS)

AF:

0.386

AC:

1859

AN:

4814

European-Finnish (FIN)

AF:

0.503

AC:

5290

AN:

10526

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.478

AC:

32442

AN:

67920

Other (OTH)

AF:

0.444

AC:

936

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1846

3691

5537

7382

9228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.361

Hom.:

1245

Bravo

AF:

0.453

Asia WGS

AF:

0.281

AC:

978

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_noAF

Benign

-0.91

CADD

Benign

6.0

(source)

DANN

Benign

0.36

PhyloP100

-0.32

PromoterAI

0.084

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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