rs5516

Positions:

• chr19-50820217-C-G
• chr19-50820217-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002257.4(KLK1):​c.433G>C​(p.Glu145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,611,396 control chromosomes in the GnomAD database, including 370,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (34332 hom., cov: 31)
  • Exomes 𝑓: 0.68 (336334 hom.)
• Consequence: KLK1 NM_002257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.07

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]

KLK1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1316266E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK1	NM_002257.4	c.433G>C	p.Glu145Gln	missense_variant	3/5	ENST00000301420.3	NP_002248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK1	ENST00000301420.3	c.433G>C	p.Glu145Gln	missense_variant	3/5	1	NM_002257.4	ENSP00000301420.1

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101698 AN: 151762 Hom.: 34293 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.689 AC: 172940 AN: 251044 Hom.: 60264 AF XY: 0.682 AC XY: 92535 AN XY: 135656

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.801

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.677 AC: 988384 AN: 1459514 Hom.: 336334 Cov.: 56 AF XY: 0.675 AC XY: 489818 AN XY: 725538

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.790

Gnomad4 ASJ exome AF: 0.614

Gnomad4 EAS exome AF: 0.782

Gnomad4 SAS exome AF: 0.634

Gnomad4 FIN exome AF: 0.675

Gnomad4 NFE exome AF: 0.676

Gnomad4 OTH exome AF: 0.671

GnomAD4 genome AF: 0.670 AC: 101794 AN: 151882 Hom.: 34332 Cov.: 31 AF XY: 0.669 AC XY: 49628 AN XY: 74222

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.672

Gnomad4 OTH AF: 0.683

Alfa AF: 0.663 Hom.: 10887

Bravo AF: 0.677

TwinsUK AF: 0.681 AC: 2526

ALSPAC AF: 0.661 AC: 2549

ESP6500AA AF: 0.629 AC: 2772

ESP6500EA AF: 0.669 AC: 5752

ExAC AF: 0.685 AC: 83160

Asia WGS AF: 0.717 AC: 2494 AN: 3478

EpiCase AF: 0.663

EpiControl AF: 0.661

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.0070
DANN	Benign	0.62
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.37	N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.23
ClinPred		0.0020	T
GERP RS		-3.9
Varity_R		0.087
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs5516; hg19: chr19-51323473; COSMIC: COSV56826320; COSMIC: COSV56826320;