chr19-50819976-T-C

Position:

• chr19-50819976-T-C

Variant summary

Our verdict is Benign. Variant got -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. 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 0.28 (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

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=8.245634E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK1	NM_002257.4	c.556A>G	p.Lys186Glu	missense_variant	4/5	ENST00000301420.3	NP_002248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK1	ENST00000301420.3	c.556A>G	p.Lys186Glu	missense_variant	4/5	1	NM_002257.4	ENSP00000301420.1

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

GnomAD3 exomes AF: 0.329 AC: 82611 AN: 251246 Hom.: 15632 AF XY: 0.318 AC XY: 43213 AN XY: 135804

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 SAS exome AF: 0.271

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

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.510

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.530

Gnomad4 SAS exome AF: 0.275

Gnomad4 FIN exome AF: 0.305

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.290

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

Gnomad4 AFR AF: 0.197

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.586

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.282

Alfa AF: 0.271 Hom.: 7503

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 v4.3

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	0.0000082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.070	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs5517; hg19: chr19-51323232; COSMIC: COSV56826308; COSMIC: COSV56826308;