19-50910546-G-C

Variant names:

• chr19-50910546-G-C
• rs198969
• NM_004917.5:c.61+132C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• amelogenesis imperfecta type 2A1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.61+132C>G		intron_variant	Intron 2 of 5	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.-237+132C>G		intron_variant	Intron 1 of 4		NP_001289890.1
KLK4	NR_126566.2	n.61+132C>G		intron_variant	Intron 1 of 4
KLK4	XM_011527545.4	c.61+132C>G		intron_variant	Intron 1 of 3		XP_011525847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.61+132C>G		intron_variant	Intron 2 of 5	1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000598305.5	n.-218+132C>G		intron_variant	Intron 1 of 4	1		ENSP00000469963.1
KLK4	ENST00000602148.1	n.61+132C>G		intron_variant	Intron 1 of 4	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

African (AFR) AF: 0.520 AC: 9177 AN: 17642

American (AMR) AF: 0.679 AC: 23525 AN: 34634

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 11565 AN: 20578

East Asian (EAS) AF: 0.141 AC: 4549 AN: 32328

South Asian (SAS) AF: 0.473 AC: 30458 AN: 64402

European-Finnish (FIN) AF: 0.500 AC: 23176 AN: 46310

Middle Eastern (MID) AF: 0.531 AC: 2255 AN: 4244

European-Non Finnish (NFE) AF: 0.538 AC: 227274 AN: 422156

Other (OTH) AF: 0.509 AC: 17404 AN: 34182

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

African (AFR) AF: 0.523 AC: 21682 AN: 41418

American (AMR) AF: 0.620 AC: 9460 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1889 AN: 3468

East Asian (EAS) AF: 0.163 AC: 843 AN: 5168

South Asian (SAS) AF: 0.445 AC: 2142 AN: 4812

European-Finnish (FIN) AF: 0.510 AC: 5381 AN: 10554

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.531 AC: 36064 AN: 67952

Other (OTH) AF: 0.506 AC: 1064 AN: 2102

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.8
DANN	Benign	0.38
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs198969; hg19: chr19-51413802; COSMIC: COSV60677030; COSMIC: COSV60677030;