19-50910546-G-C

Position:

• chr19-50910546-G-C

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+132C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 828,416 control chromosomes in the GnomAD database, including 115,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21268 hom., cov: 31)
  • Exomes 𝑓: 0.52 (94072 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.424

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=-0.91).
• BP6: Variant 19-50910546-G-C is Benign according to our data. Variant chr19-50910546-G-C is described in ClinVar as [Benign]. Clinvar id is 1263437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK4	NM_004917.5	c.61+132C>G		intron_variant		ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.-237+132C>G		intron_variant			NP_001289890.1
KLK4	XM_011527545.4	c.61+132C>G		intron_variant			XP_011525847.1
KLK4	NR_126566.2	n.61+132C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.61+132C>G		intron_variant		1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000598305.5	n.-218+132C>G		intron_variant		1		ENSP00000469963.1
KLK4	ENST00000602148.1	n.61+132C>G		intron_variant		1		ENSP00000472091.1

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79125 AN: 151820 Hom.: 21246 Cov.: 31

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.512

GnomAD4 exome AF: 0.516 AC: 349383 AN: 676476 Hom.: 94072 AF XY: 0.515 AC XY: 184050 AN XY: 357584

Gnomad4 AFR exome AF: 0.520

Gnomad4 AMR exome AF: 0.679

Gnomad4 ASJ exome AF: 0.562

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.538

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.521 AC: 79186 AN: 151940 Hom.: 21268 Cov.: 31 AF XY: 0.522 AC XY: 38741 AN XY: 74240

Gnomad4 AFR AF: 0.523

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.163

Gnomad4 SAS AF: 0.445

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.531

Gnomad4 OTH AF: 0.506

Alfa AF: 0.394 Hom.: 1052

Bravo AF: 0.528

Asia WGS AF: 0.305 AC: 1066 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	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.8
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs198969; hg19: chr19-51413802; COSMIC: COSV60677030; COSMIC: COSV60677030;