chr19-50910072-A-G

Variant names:

• chr19-50910072-A-G
• rs198968
• NM_004917.5:c.61+606T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004917.5(KLK4):​c.61+606T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.788 in 151,792 control chromosomes in the GnomAD database, including 47,969 homozygotes. 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 0.79 (47969 hom., cov: 29)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.520
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.61+606T>C		intron_variant	Intron 2 of 5	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.-237+606T>C		intron_variant	Intron 1 of 4		NP_001289890.1
KLK4	NR_126566.2	n.61+606T>C		intron_variant	Intron 1 of 4
KLK4	XM_011527545.4	c.61+606T>C		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+606T>C		intron_variant	Intron 2 of 5	1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000598305.5	n.-218+606T>C		intron_variant	Intron 1 of 4	1		ENSP00000469963.1
KLK4	ENST00000602148.1	n.61+606T>C		intron_variant	Intron 1 of 4	1		ENSP00000472091.1

Frequencies

GnomAD3 genomes AF: 0.788 AC: 119567 AN: 151672 Hom.: 47924 Cov.: 29

Gnomad AFR AF: 0.831

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.773

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.898

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.815

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.788 AC: 119676 AN: 151792 Hom.: 47969 Cov.: 29 AF XY: 0.784 AC XY: 58165 AN XY: 74180

African (AFR) AF: 0.831 AC: 34367 AN: 41332

American (AMR) AF: 0.773 AC: 11809 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2602 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1641 AN: 5156

South Asian (SAS) AF: 0.676 AC: 3241 AN: 4796

European-Finnish (FIN) AF: 0.782 AC: 8247 AN: 10550

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55022 AN: 67908

Other (OTH) AF: 0.811 AC: 1705 AN: 2102

Alfa AF: 0.809 Hom.: 61283

Bravo AF: 0.787

Asia WGS AF: 0.508 AC: 1771 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs198968; hg19: chr19-51413328;