rs2659058

Variant names:

• chr19-50822850-C-T
• rs2659058
• NM_002257.4:c.46+853G>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.46+853G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.683 in 979,162 control chromosomes in the GnomAD database, including 229,176 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 0.69 (36632 hom., cov: 30)
  • Exomes 𝑓: 0.68 (192544 hom.)
• Consequence: KLK1 NM_002257.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.791
• Publications: 6 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 (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK1	NM_002257.4	MANE Select	c.46+853G>A		intron	N/A	NP_002248.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK1	ENST00000301420.3	TSL:1 MANE Select	c.46+853G>A		intron	N/A	ENSP00000301420.1
	KLK1	ENST00000878924.1		c.46+853G>A		intron	N/A	ENSP00000548983.1
	KLK1	ENST00000593325.5	TSL:2	n.122+27G>A		intron	N/A	ENSP00000472939.1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105135 AN: 151740 Hom.: 36582 Cov.: 30

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.633

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.680

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.679

Gnomad OTH AF: 0.698

GnomAD2 exomes AF: 0.669 AC: 119 AN: 178 AF XY: 0.615

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 1.00

Gnomad ASJ exome AF: 0.750

Gnomad EAS exome AF: 0.667

Gnomad FIN exome AF: 0.500

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.681 AC: 563722 AN: 827302 Hom.: 192544 Cov.: 17 AF XY: 0.682 AC XY: 260520 AN XY: 382264

African (AFR) AF: 0.687 AC: 10773 AN: 15686

American (AMR) AF: 0.723 AC: 709 AN: 980

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 3183 AN: 5128

East Asian (EAS) AF: 0.791 AC: 2854 AN: 3608

South Asian (SAS) AF: 0.618 AC: 10104 AN: 16340

European-Finnish (FIN) AF: 0.698 AC: 226 AN: 324

Middle Eastern (MID) AF: 0.642 AC: 1029 AN: 1602

European-Non Finnish (NFE) AF: 0.683 AC: 516653 AN: 756494

Other (OTH) AF: 0.670 AC: 18191 AN: 27140

GnomAD4 genome AF: 0.693 AC: 105243 AN: 151860 Hom.: 36632 Cov.: 30 AF XY: 0.692 AC XY: 51336 AN XY: 74210

African (AFR) AF: 0.702 AC: 29044 AN: 41398

American (AMR) AF: 0.742 AC: 11327 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 2194 AN: 3466

East Asian (EAS) AF: 0.800 AC: 4103 AN: 5128

South Asian (SAS) AF: 0.633 AC: 3039 AN: 4798

European-Finnish (FIN) AF: 0.680 AC: 7182 AN: 10560

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

European-Non Finnish (NFE) AF: 0.679 AC: 46100 AN: 67932

Other (OTH) AF: 0.701 AC: 1475 AN: 2104

Alfa AF: 0.678 Hom.: 4704

Bravo AF: 0.702

Asia WGS AF: 0.707 AC: 2457 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.0
DANN	Benign	0.50
PhyloP100		-0.79
Mutation Taster		=100/0	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: rs2659058; hg19: chr19-51326106;