19-50821713-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002257.4(KLK1):c.205G>A(p.Asp69Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,605,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: KLK1 NM_002257.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005666
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010896683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK1	NM_002257.4	c.205G>A	p.Asp69Asn	missense_variant, splice_region_variant	2/5	ENST00000301420.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK1	ENST00000301420.3	c.205G>A	p.Asp69Asn	missense_variant, splice_region_variant	2/5	1	NM_002257.4	P1
KLK1	ENST00000593859.5	n.244G>A		splice_region_variant, non_coding_transcript_exon_variant	2/4	2
KLK1	ENST00000593325.5	c.*1014G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/6	2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000307 AC: 75 AN: 244646 Hom.: 0 AF XY: 0.000325 AC XY: 43 AN XY: 132212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000657

Gnomad SAS exome AF: 0.0000678

Gnomad FIN exome AF: 0.00108

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.00152

GnomAD4 exome AF: 0.000137 AC: 199 AN: 1453466 Hom.: 0 Cov.: 31 AF XY: 0.000137 AC XY: 99 AN XY: 722360

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000708

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00113

Gnomad4 NFE exome AF: 0.0000695

Gnomad4 OTH exome AF: 0.000517

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152218 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000153 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000395 AC: 48

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.205G>A (p.D69N) alteration is located in exon 2 (coding exon 2) of the KLK1 gene. This alteration results from a G to A substitution at nucleotide position 205, causing the aspartic acid (D) at amino acid position 69 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.49
Dann	Benign	0.73
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.051	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.26	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.013
Sift	Benign	0.32	T
Sift4G	Benign	0.63	T
Polyphen		0.040	B
Vest4		0.19
MVP		0.12
MPC		0.22
ClinPred		0.0075	T
GERP RS		-1.3
Varity_R		0.19
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.0060
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

Other links and lift over

dbSNP: rs146975864; hg19: chr19-51324969;