chr19-50820240-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_002257.4(KLK1):c.410T>C(p.Val137Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
KLK1
NM_002257.4 missense
NM_002257.4 missense
Scores
2
9
8
Clinical Significance
Conservation
PhyloP100: 2.59
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.939
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KLK1 | NM_002257.4 | c.410T>C | p.Val137Ala | missense_variant | 3/5 | ENST00000301420.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KLK1 | ENST00000301420.3 | c.410T>C | p.Val137Ala | missense_variant | 3/5 | 1 | NM_002257.4 | P1 | |
KLK1 | ENST00000593859.5 | n.449T>C | non_coding_transcript_exon_variant | 3/4 | 2 | ||||
KLK1 | ENST00000596300.1 | n.610T>C | non_coding_transcript_exon_variant | 1/3 | 2 | ||||
KLK1 | ENST00000593325.5 | c.*1219T>C | 3_prime_UTR_variant, NMD_transcript_variant | 4/6 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151964Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251404Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461714Hom.: 0 Cov.: 54 AF XY: 0.00000138 AC XY: 1AN XY: 727114
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 15, 2021 | The c.410T>C (p.V137A) alteration is located in exon 3 (coding exon 3) of the KLK1 gene. This alteration results from a T to C substitution at nucleotide position 410, causing the valine (V) at amino acid position 137 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Benign
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of stability (P = 0.0055);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at