19-50819965-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002257.4(KLK1):c.567C>T(p.His189=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,614,056 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (47 hom.)
• Consequence: KLK1 NM_002257.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.729

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-50819965-G-A is Benign according to our data. Variant chr19-50819965-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 708033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.729 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KLK1	NM_002257.4	c.567C>T	p.His189=	synonymous_variant	4/5	ENST00000301420.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KLK1	ENST00000301420.3	c.567C>T	p.His189=	synonymous_variant	4/5	1	NM_002257.4	P1
KLK1	ENST00000593859.5	n.724C>T		non_coding_transcript_exon_variant	3/4	2
KLK1	ENST00000596300.1	n.767C>T		non_coding_transcript_exon_variant	2/3	2
KLK1	ENST00000593325.5	c.*1376C>T		3_prime_UTR_variant, NMD_transcript_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 561 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00650

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00325 AC: 818 AN: 251416 Hom.: 3 AF XY: 0.00322 AC XY: 438 AN XY: 135902

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00571

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00609 AC: 8905 AN: 1461742 Hom.: 47 Cov.: 31 AF XY: 0.00588 AC XY: 4275 AN XY: 727178

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00744

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00368 AC: 560 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74478

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00648

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00511 Hom.: 2

Bravo AF: 0.00395

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KLK1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.7
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs3212857; hg19: chr19-51323221;