rs5516

Variant names:

• chr19-50820217-C-G
• rs5516
• NM_002257.4:c.433G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50820217-C-G
• chr19-50820217-C-T

Variant summary

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

The NM_002257.4(KLK1):​c.433G>C​(p.Glu145Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 1,611,396 control chromosomes in the GnomAD database, including 370,666 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 0.67 (34332 hom., cov: 31)
  • Exomes 𝑓: 0.68 (336334 hom.)
• Consequence: KLK1 NM_002257.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.07
• Publications: 58 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=1.1316266E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 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.433G>C	p.Glu145Gln	missense	Exon 3 of 5	NP_002248.1	P06870-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK1	ENST00000301420.3	TSL:1 MANE Select	c.433G>C	p.Glu145Gln	missense	Exon 3 of 5	ENSP00000301420.1	P06870-1
	KLK1	ENST00000878924.1		c.433G>C	p.Glu145Gln	missense	Exon 3 of 5	ENSP00000548983.1
	KLK1	ENST00000593325.5	TSL:2	n.*1242G>C		non_coding_transcript_exon	Exon 4 of 6	ENSP00000472939.1	M0R318

Frequencies

GnomAD3 genomes AF: 0.670 AC: 101698 AN: 151762 Hom.: 34293 Cov.: 31

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.672

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.689 AC: 172940 AN: 251044 AF XY: 0.682

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.801

Gnomad ASJ exome AF: 0.617

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.677 AC: 988384 AN: 1459514 Hom.: 336334 Cov.: 56 AF XY: 0.675 AC XY: 489818 AN XY: 725538

African (AFR) AF: 0.630 AC: 21068 AN: 33432

American (AMR) AF: 0.790 AC: 35289 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 16042 AN: 26106

East Asian (EAS) AF: 0.782 AC: 30962 AN: 39616

South Asian (SAS) AF: 0.634 AC: 54648 AN: 86194

European-Finnish (FIN) AF: 0.675 AC: 36021 AN: 53400

Middle Eastern (MID) AF: 0.640 AC: 3685 AN: 5756

European-Non Finnish (NFE) AF: 0.676 AC: 750196 AN: 1110050

Other (OTH) AF: 0.671 AC: 40473 AN: 60276

GnomAD4 genome AF: 0.670 AC: 101794 AN: 151882 Hom.: 34332 Cov.: 31 AF XY: 0.669 AC XY: 49628 AN XY: 74222

African (AFR) AF: 0.637 AC: 26370 AN: 41398

American (AMR) AF: 0.728 AC: 11119 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2180 AN: 3472

East Asian (EAS) AF: 0.795 AC: 4098 AN: 5152

South Asian (SAS) AF: 0.657 AC: 3157 AN: 4806

European-Finnish (FIN) AF: 0.663 AC: 6967 AN: 10514

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.672 AC: 45701 AN: 67960

Other (OTH) AF: 0.683 AC: 1437 AN: 2104

Alfa AF: 0.663 Hom.: 10887

Bravo AF: 0.677

TwinsUK AF: 0.681 AC: 2526

ALSPAC AF: 0.661 AC: 2549

ESP6500AA AF: 0.629 AC: 2772

ESP6500EA AF: 0.669 AC: 5752

ExAC AF: 0.685 AC: 83160

Asia WGS AF: 0.717 AC: 2494 AN: 3478

EpiCase AF: 0.663

EpiControl AF: 0.661

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.0070
DANN	Benign	0.62
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.37	N
PhyloP100		-3.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.89	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.23
ClinPred		0.0020	T
GERP RS		-3.9
Varity_R		0.087
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs5516; hg19: chr19-51323473; COSMIC: COSV56826320; COSMIC: COSV56826320;