chr19-50820245-A-G

Variant names:

• chr19-50820245-A-G
• rs1054713
• NM_002257.4:c.405T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002257.4(KLK1):​c.405T>C​(p.Asp135Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,613,394 control chromosomes in the GnomAD database, including 375,506 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.70 (37461 hom., cov: 30)
  • Exomes 𝑓: 0.68 (338045 hom.)
• Consequence: KLK1 NM_002257.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.10
• Publications: 35 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP7: Synonymous conserved (PhyloP=-5.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK1	NM_002257.4	c.405T>C	p.Asp135Asp	synonymous_variant	Exon 3 of 5	ENST00000301420.3	NP_002248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK1	ENST00000301420.3	c.405T>C	p.Asp135Asp	synonymous_variant	Exon 3 of 5	1	NM_002257.4	ENSP00000301420.1

Frequencies

GnomAD3 genomes AF: 0.700 AC: 106220 AN: 151704 Hom.: 37413 Cov.: 30

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.701

GnomAD2 exomes AF: 0.696 AC: 174911 AN: 251386 AF XY: 0.686

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.618

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.671

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.678 AC: 991520 AN: 1461572 Hom.: 338045 Cov.: 54 AF XY: 0.676 AC XY: 491301 AN XY: 727070

African (AFR) AF: 0.741 AC: 24802 AN: 33472

American (AMR) AF: 0.795 AC: 35560 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.615 AC: 16072 AN: 26130

East Asian (EAS) AF: 0.782 AC: 31031 AN: 39694

South Asian (SAS) AF: 0.631 AC: 54446 AN: 86244

European-Finnish (FIN) AF: 0.673 AC: 35947 AN: 53414

Middle Eastern (MID) AF: 0.641 AC: 3698 AN: 5766

European-Non Finnish (NFE) AF: 0.674 AC: 749125 AN: 1111748

Other (OTH) AF: 0.676 AC: 40839 AN: 60384

GnomAD4 genome AF: 0.700 AC: 106326 AN: 151822 Hom.: 37461 Cov.: 30 AF XY: 0.698 AC XY: 51784 AN XY: 74174

African (AFR) AF: 0.745 AC: 30809 AN: 41370

American (AMR) AF: 0.740 AC: 11318 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4079 AN: 5132

South Asian (SAS) AF: 0.654 AC: 3145 AN: 4808

European-Finnish (FIN) AF: 0.663 AC: 6953 AN: 10494

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.671 AC: 45587 AN: 67944

Other (OTH) AF: 0.704 AC: 1486 AN: 2112

Alfa AF: 0.672 Hom.: 62268

Bravo AF: 0.712

Asia WGS AF: 0.721 AC: 2507 AN: 3478

EpiCase AF: 0.662

EpiControl AF: 0.659

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.017
DANN	Benign	0.31
PhyloP100		-5.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1054713; hg19: chr19-51323501; COSMIC: COSV56826329; COSMIC: COSV56826329;