Genetic Variant KLK1:c.46+853G>A (chr19-50822850-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_002257.4(KLK1):c.46+853G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 979,162 control chromosomes in the GnomAD database, including 229,176 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 0.69 ( 36632 hom., cov: 30)

Exomes 𝑓: 0.68 ( 192544 hom. )

Consequence

KLK1
NM_002257.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.791

Variant links:

Genes affected

KLK1 (HGNC:6357): (kallikrein 1) 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. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. This protein is functionally conserved in its capacity to release the vasoactive peptide, Lys-bradykinin, from low molecular weight kininogen. [provided by RefSeq, Jul 2008]

KLK1 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=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK1	NM_002257.4 link	c.46+853G>A		intron_variant	Intron 1 of 4	ENST00000301420.3	NP_002248.1	P06870-1A0A1R3UCD2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
KLK1	ENST00000301420.3 link	c.46+853G>A	intron_variant	Intron 1 of 4	1	NM_002257.4	ENSP00000301420.1	P06870-1
KLK1	ENST00000593325.5 link	n.122+27G>A	intron_variant	Intron 2 of 5	2		ENSP00000472939.1	M0R318
KLK1	ENST00000593859.5 link	n.85+853G>A	intron_variant	Intron 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.693

AC:

105135

AN:

151740

Hom.:

36582

Cov.:

show subpopulations

Gnomad AFR

AF:

0.701

Gnomad AMI

AF:

0.658

Gnomad AMR

AF:

0.741

Gnomad ASJ

AF:

0.633

Gnomad EAS

AF:

0.800

Gnomad SAS

AF:

0.633

Gnomad FIN

AF:

0.680

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.679

Gnomad OTH

AF:

0.698

GnomAD2 exomes

AF:

0.669

AC:

119

AN:

178

AF XY:

0.615

show subpopulations

Gnomad AFR exome

AF:

0.684

Gnomad AMR exome

AF:

1.00

Gnomad ASJ exome

AF:

0.750

Gnomad EAS exome

AF:

0.667

Gnomad FIN exome

AF:

0.500

Gnomad NFE exome

AF:

0.676

Gnomad OTH exome

AF:

0.571

GnomAD4 exome

AF:

0.681

AC:

563722

AN:

827302

Hom.:

192544

Cov.:

AF XY:

0.682

AC XY:

260520

AN XY:

382264

show subpopulations

Gnomad4 AFR exome

AF:

0.687

AC:

10773

AN:

15686

Gnomad4 AMR exome

AF:

0.723

AC:

709

AN:

980

Gnomad4 ASJ exome

AF:

0.621

AC:

3183

AN:

5128

Gnomad4 EAS exome

AF:

0.791

AC:

2854

AN:

3608

Gnomad4 SAS exome

AF:

0.618

AC:

10104

AN:

16340

Gnomad4 FIN exome

AF:

0.698

AC:

226

AN:

324

Gnomad4 NFE exome

AF:

0.683

AC:

516653

AN:

756494

Gnomad4 Remaining exome

AF:

0.670

AC:

18191

AN:

27140

Heterozygous variant carriers

8195

16390

24585

32780

40975

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

18068

36136

54204

72272

90340

<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:

0.693

AC:

105243

AN:

151860

Hom.:

36632

Cov.:

AF XY:

0.692

AC XY:

51336

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.702

AC:

0.70158

AN:

0.70158

Gnomad4 AMR

AF:

0.742

AC:

0.741878

AN:

0.741878

Gnomad4 ASJ

AF:

0.633

AC:

0.633006

AN:

0.633006

Gnomad4 EAS

AF:

0.800

AC:

0.800117

AN:

0.800117

Gnomad4 SAS

AF:

0.633

AC:

0.633389

AN:

0.633389

Gnomad4 FIN

AF:

0.680

AC:

0.680114

AN:

0.680114

Gnomad4 NFE

AF:

0.679

AC:

0.67862

AN:

0.67862

Gnomad4 OTH

AF:

0.701

AC:

0.701046

AN:

0.701046

Heterozygous variant carriers

1646

3291

4937

6582

8228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.678

Hom.:

4704

Bravo

AF:

0.702

Asia WGS

AF:

0.707

AC:

2457

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

5.0

DANN

Benign

0.50

Mutation Taster

=100/0

polymorphism (auto)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over