Genetic Variant NM_015596.3:c.749G>C (chr19-51056672-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_015596.3(KLK13):c.749G>C(p.Arg250Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R250H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KLK13
NM_015596.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0420

Publications

0 publications found

Variant links:

Genes affected

KLK13 (HGNC:6361): (kallikrein related peptidase 13) 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. Expression of this gene is regulated by steroid hormones and may be useful as a marker for breast cancer. [provided by RefSeq, Jan 2017]

KLK13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.877

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015596.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK13	NM_015596.3	MANE Select	c.749G>C	p.Arg250Pro	missense	Exon 5 of 5	NP_056411.1	Q9UKR3-1
KLK13	NM_001348177.2		c.530G>C	p.Arg177Pro	missense	Exon 5 of 5	NP_001335106.1	Q86VI7
KLK13	NM_001348178.2		c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	NP_001335107.1	Q9UKR3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KLK13	ENST00000595793.6	TSL:1 MANE Select	c.749G>C	p.Arg250Pro	missense	Exon 5 of 5	ENSP00000470555.1	Q9UKR3-1
KLK13	ENST00000595547.5	TSL:1	c.530G>C	p.Arg177Pro	missense	Exon 5 of 5	ENSP00000470245.1	Q86VI7
KLK13	ENST00000335422.3	TSL:1	c.293G>C	p.Arg98Pro	missense	Exon 3 of 3	ENSP00000334079.3	Q9UKR3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

0.031

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.88

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

2.9

PhyloP100

-0.042

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Benign

0.071

Polyphen

0.99

Vest4

0.67

MutPred

0.80

Loss of MoRF binding (P = 0.0082)

MVP

0.93

MPC

0.61

ClinPred

0.98

GERP RS

3.4

Varity_R

0.93

gMVP

0.97

Mutation Taster

=82/18

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over