rs2242669

Positions:

• chr19-50910534-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004917.5(KLK4):​c.61+144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 775,154 control chromosomes in the GnomAD database, including 13,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3518 hom., cov: 31)
  • Exomes 𝑓: 0.17 (10017 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.47

Genes affected

KLK4 (HGNC:6365): (kallikrein related peptidase 4) 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. In some tissues its expression is hormonally regulated. The expression pattern of a similar mouse protein in murine developing teeth supports a role for the protein in the degradation of enamel proteins. Several transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Dec 2014]

KLK4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-50910534-G-A is Benign according to our data. Variant chr19-50910534-G-A is described in ClinVar as [Benign]. Clinvar id is 1242612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK4	NM_004917.5	c.61+144C>T		intron_variant		ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.-237+144C>T		intron_variant			NP_001289890.1
KLK4	XM_011527545.4	c.61+144C>T		intron_variant			XP_011525847.1
KLK4	NR_126566.2	n.61+144C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.61+144C>T		intron_variant		1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000598305.5	n.-218+144C>T		intron_variant		1		ENSP00000469963.1
KLK4	ENST00000602148.1	n.61+144C>T		intron_variant		1		ENSP00000472091.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31520 AN: 151908 Hom.: 3505 Cov.: 31

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.213

GnomAD4 exome AF: 0.174 AC: 108360 AN: 623128 Hom.: 10017 AF XY: 0.174 AC XY: 57883 AN XY: 331828

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.191

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.192

GnomAD4 genome AF: 0.208 AC: 31567 AN: 152026 Hom.: 3518 Cov.: 31 AF XY: 0.206 AC XY: 15297 AN XY: 74284

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.214

Alfa AF: 0.186 Hom.: 566

Bravo AF: 0.210

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.6
DANN	Benign	0.45

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: rs2242669; hg19: chr19-51413790; COSMIC: COSV60676515; COSMIC: COSV60676515;