dbSNP rs2978642: KLK4:c.61+28T>A (chr19-50910650-A-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004917.5(KLK4):c.61+28T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,547,322 control chromosomes in the GnomAD database, including 55,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 9489 hom., cov: 31)

Exomes 𝑓: 0.25 ( 46291 hom. )

Consequence

KLK4
NM_004917.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.895

Publications

13 publications found

Variant links:

Genes affected

KLK4 (HGNC:6365): (kallikrein related peptidase 4) 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. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Dec 2014]

KLK4 Gene-Disease associations (from GenCC):

amelogenesis imperfecta type 2A1
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KLK4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 19-50910650-A-T is Benign according to our data. Variant chr19-50910650-A-T is described in ClinVar as Benign. ClinVar VariationId is 1286882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004917.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KLK4	NM_004917.5	MANE Select	c.61+28T>A	intron	N/A	NP_004908.4
KLK4	NM_001302961.2		c.-237+28T>A	intron	N/A	NP_001289890.1
KLK4	NR_126566.2		n.61+28T>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLK4	ENST00000324041.6	TSL:1 MANE Select	c.61+28T>A	intron	N/A	ENSP00000326159.1	A0A0C4DFQ5
KLK4	ENST00000598305.5	TSL:1	n.-218+28T>A	intron	N/A	ENSP00000469963.1	M0QYN5
KLK4	ENST00000602148.1	TSL:1	n.61+28T>A	intron	N/A	ENSP00000472091.1	Q5BQA0

Frequencies

GnomAD3 genomes

AF:

0.326

AC:

49488

AN:

151832

Hom.:

9462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.540

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.262

Gnomad ASJ

AF:

0.222

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.325

GnomAD2 exomes

AF:

0.266

AC:

42385

AN:

159112

AF XY:

0.266

show subpopulations

Gnomad AFR exome

AF:

0.543

Gnomad AMR exome

AF:

0.217

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.240

Gnomad FIN exome

AF:

0.215

Gnomad NFE exome

AF:

0.245

Gnomad OTH exome

AF:

0.262

GnomAD4 exome

AF:

0.251

AC:

349958

AN:

1395372

Hom.:

46291

Cov.:

AF XY:

0.253

AC XY:

173964

AN XY:

688692

show subpopulations

African (AFR)

AF:

0.549

AC:

17329

AN:

31580

American (AMR)

AF:

0.228

AC:

8154

AN:

35754

Ashkenazi Jewish (ASJ)

AF:

0.217

AC:

5457

AN:

25170

East Asian (EAS)

AF:

0.216

AC:

7756

AN:

35850

South Asian (SAS)

AF:

0.330

AC:

26159

AN:

79196

European-Finnish (FIN)

AF:

0.219

AC:

10803

AN:

49414

Middle Eastern (MID)

AF:

0.334

AC:

1899

AN:

5686

European-Non Finnish (NFE)

AF:

0.239

AC:

256782

AN:

1074808

Other (OTH)

AF:

0.270

AC:

15619

AN:

57914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

13789

27578

41367

55156

68945

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8930

17860

26790

35720

44650

<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:

0.326

AC:

49561

AN:

151950

Hom.:

9489

Cov.:

AF XY:

0.322

AC XY:

23929

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.540

AC:

22368

AN:

41404

American (AMR)

AF:

0.262

AC:

3991

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

770

AN:

3468

East Asian (EAS)

AF:

0.233

AC:

1198

AN:

5150

South Asian (SAS)

AF:

0.323

AC:

1554

AN:

4814

European-Finnish (FIN)

AF:

0.206

AC:

2179

AN:

10586

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16433

AN:

67964

Other (OTH)

AF:

0.326

AC:

686

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1554

3108

4661

6215

7769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

474

948

1422

1896

2370

<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:

0.201

Hom.:

652

Bravo

AF:

0.337

Asia WGS

AF:

0.291

AC:

1013

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

5.8

(source)

DANN

Benign

0.83

PhyloP100

-0.90

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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