Genetic Variant KLK4:c.613-56C>A (chr19-50907142-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004917.5(KLK4):c.613-56C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,577,328 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

KLK4
NM_004917.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.352

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

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

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.613-56C>A	intron	N/A	NP_004908.4
KLK4	NM_001302961.2		c.328-56C>A	intron	N/A	NP_001289890.1
KLK4	NR_126566.2		n.602-56C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KLK4	ENST00000324041.6	TSL:1 MANE Select	c.613-56C>A	intron	N/A	ENSP00000326159.1	A0A0C4DFQ5
KLK4	ENST00000431178.2	TSL:1	c.329-56C>A	intron	N/A	ENSP00000399448.2	Q9Y5K2-2
KLK4	ENST00000598305.5	TSL:1	n.*108-56C>A	intron	N/A	ENSP00000469963.1	M0QYN5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

1425034

Hom.:

AF XY:

0.0000169

AC XY:

AN XY:

711142

show subpopulations

African (AFR)

AF:

0.000734

AC:

AN:

32688

American (AMR)

AF:

0.00

AC:

AN:

44508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25944

East Asian (EAS)

AF:

0.00

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

85398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53210

Middle Eastern (MID)

AF:

0.000206

AC:

AN:

4862

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079944

Other (OTH)

AF:

0.0000339

AC:

AN:

58998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000105

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.8

(source)

DANN

Benign

0.36

PhyloP100

-0.35

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