19-50820420-C-T

Variant names:

• chr19-50820420-C-T
• rs5515
• NM_002257.4:c.230G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002257.4(KLK1):​c.230G>A​(p.Arg77His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 1,609,342 control chromosomes in the GnomAD database, including 1,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Affects (no stars).

• Frequency:
  • Genomes: 𝑓 0.050 (249 hom., cov: 28)
  • Exomes 𝑓: 0.034 (1043 hom.)
• Consequence: KLK1 NM_002257.4 missense
• Clinical Significance: Affects no assertion criteria provided O:1
• Conservation: PhyloP100: -0.174
• Publications: 33 publications found

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 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0102929175).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002257.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK1	NM_002257.4	MANE Select	c.230G>A	p.Arg77His	missense	Exon 3 of 5	NP_002248.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK1	ENST00000301420.3	TSL:1 MANE Select	c.230G>A	p.Arg77His	missense	Exon 3 of 5	ENSP00000301420.1
	KLK1	ENST00000593325.5	TSL:2	n.*1039G>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000472939.1
	KLK1	ENST00000593859.5	TSL:2	n.269G>A		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0496 AC: 7431 AN: 149908 Hom.: 248 Cov.: 28

Gnomad AFR AF: 0.0998

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0315

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0513

GnomAD2 exomes AF: 0.0312 AC: 7765 AN: 248920 AF XY: 0.0301

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0230

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00742

Gnomad NFE exome AF: 0.0370

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0341 AC: 49813 AN: 1459322 Hom.: 1043 Cov.: 36 AF XY: 0.0332 AC XY: 24114 AN XY: 725686

African (AFR) AF: 0.104 AC: 3474 AN: 33456

American (AMR) AF: 0.0276 AC: 1232 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 617 AN: 25996

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39642

South Asian (SAS) AF: 0.0140 AC: 1207 AN: 85914

European-Finnish (FIN) AF: 0.00877 AC: 468 AN: 53336

Middle Eastern (MID) AF: 0.0429 AC: 247 AN: 5756

European-Non Finnish (NFE) AF: 0.0364 AC: 40440 AN: 1110318

Other (OTH) AF: 0.0353 AC: 2127 AN: 60292

GnomAD4 genome AF: 0.0496 AC: 7440 AN: 150020 Hom.: 249 Cov.: 28 AF XY: 0.0468 AC XY: 3414 AN XY: 73014

African (AFR) AF: 0.0997 AC: 4050 AN: 40616

American (AMR) AF: 0.0411 AC: 612 AN: 14896

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 109 AN: 3462

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5062

South Asian (SAS) AF: 0.0116 AC: 55 AN: 4728

European-Finnish (FIN) AF: 0.00698 AC: 71 AN: 10170

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0351 AC: 2379 AN: 67792

Other (OTH) AF: 0.0507 AC: 106 AN: 2090

Alfa AF: 0.0395 Hom.: 567

Bravo AF: 0.0549

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.0971 AC: 428

ESP6500EA AF: 0.0360 AC: 310

ExAC AF: 0.0331 AC: 4017

Asia WGS AF: 0.00808 AC: 30 AN: 3478

EpiCase AF: 0.0380

EpiControl AF: 0.0404

ClinVar

Significance: Affects

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Kallikrein, decreased urinary activity of Other:1

Mar 01, 2005

OMIM

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.17
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.010	D
Sift4G	Benign	0.12	T
Polyphen		0.81	P
Vest4		0.13
MPC		0.54
ClinPred		0.027	T
GERP RS		-0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.56
gMVP		0.31
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5515; hg19: chr19-51323676; COSMIC: COSV56826883; COSMIC: COSV56826883;