19-50910546-G-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004917.5(KLK4):​c.61+132C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 829,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004917.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	NM_004917.5	MANE Select	c.61+132C>A		intron	N/A	NP_004908.4
	KLK4	NM_001302961.2		c.-237+132C>A		intron	N/A	NP_001289890.1
	KLK4	NR_126566.2		n.61+132C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.61+132C>A		intron	N/A	ENSP00000326159.1
	KLK4	ENST00000598305.5	TSL:1	n.-218+132C>A		intron	N/A	ENSP00000469963.1
	KLK4	ENST00000602148.1	TSL:1	n.61+132C>A		intron	N/A	ENSP00000472091.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151910 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 12 AN: 677394 Hom.: 0 AF XY: 0.0000112 AC XY: 4 AN XY: 358048

African (AFR) AF: 0.00 AC: 0 AN: 17666

American (AMR) AF: 0.00 AC: 0 AN: 34646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20596

East Asian (EAS) AF: 0.00 AC: 0 AN: 32358

South Asian (SAS) AF: 0.00 AC: 0 AN: 64420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4244

European-Non Finnish (NFE) AF: 0.0000213 AC: 9 AN: 422866

Other (OTH) AF: 0.0000877 AC: 3 AN: 34214

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151910 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74168

African (AFR) AF: 0.0000726 AC: 3 AN: 41328

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 1052

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.51
PhyloP100		-0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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;