chr19-50819976-T-C

Variant names:

• chr19-50819976-T-C
• rs5517
• NM_002257.4:c.556A>G

Variant summary

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

The NM_002257.4(KLK1):​c.556A>G​(p.Lys186Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 1,613,644 control chromosomes in the GnomAD database, including 70,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6484 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64389 hom.)
• Consequence: KLK1 NM_002257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.951
• Publications: 46 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=8.245634E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 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.556A>G	p.Lys186Glu	missense	Exon 4 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.556A>G	p.Lys186Glu	missense	Exon 4 of 5	ENSP00000301420.1
	KLK1	ENST00000593325.5	TSL:2	n.*1365A>G		non_coding_transcript_exon	Exon 5 of 6	ENSP00000472939.1
	KLK1	ENST00000593859.5	TSL:2	n.713A>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42156 AN: 152034 Hom.: 6462 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.273

GnomAD2 exomes AF: 0.329 AC: 82611 AN: 251246 AF XY: 0.318

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.587

Gnomad FIN exome AF: 0.304

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.289 AC: 421873 AN: 1461492 Hom.: 64389 Cov.: 36 AF XY: 0.287 AC XY: 208566 AN XY: 727072

African (AFR) AF: 0.192 AC: 6438 AN: 33478

American (AMR) AF: 0.510 AC: 22774 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6504 AN: 26130

East Asian (EAS) AF: 0.530 AC: 21020 AN: 39692

South Asian (SAS) AF: 0.275 AC: 23759 AN: 86246

European-Finnish (FIN) AF: 0.305 AC: 16286 AN: 53412

Middle Eastern (MID) AF: 0.223 AC: 1283 AN: 5766

European-Non Finnish (NFE) AF: 0.276 AC: 306274 AN: 1111684

Other (OTH) AF: 0.290 AC: 17535 AN: 60386

GnomAD4 genome AF: 0.277 AC: 42218 AN: 152152 Hom.: 6484 Cov.: 32 AF XY: 0.282 AC XY: 20955 AN XY: 74406

African (AFR) AF: 0.197 AC: 8161 AN: 41506

American (AMR) AF: 0.396 AC: 6063 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 929 AN: 3472

East Asian (EAS) AF: 0.586 AC: 3023 AN: 5162

South Asian (SAS) AF: 0.283 AC: 1366 AN: 4822

European-Finnish (FIN) AF: 0.303 AC: 3214 AN: 10594

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18620 AN: 67984

Other (OTH) AF: 0.282 AC: 594 AN: 2108

Alfa AF: 0.277 Hom.: 18108

Bravo AF: 0.284

TwinsUK AF: 0.279 AC: 1034

ALSPAC AF: 0.265 AC: 1023

ESP6500AA AF: 0.196 AC: 865

ESP6500EA AF: 0.269 AC: 2310

ExAC AF: 0.320 AC: 38800

Asia WGS AF: 0.445 AC: 1547 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.4
DANN	Benign	0.37
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.042	T
MetaRNN	Benign	0.0000083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.070	N
PhyloP100		-0.95
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.011	B
Vest4		0.033
MPC		0.32
ClinPred		0.0024	T
GERP RS		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.46
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs5517; hg19: chr19-51323232; COSMIC: COSV56826308; COSMIC: COSV56826308;