rs2242670

Variant names:

• chr19-50909059-A-G
• rs2242670
• NM_004917.5:c.224+193T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50909059-A-G
• chr19-50909059-A-T

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.224+193T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 1,477,836 control chromosomes in the GnomAD database, including 206,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20305 hom., cov: 30)
  • Exomes 𝑓: 0.53 (186073 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.43
• Publications: 11 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.96).
• BP6: Variant 19-50909059-A-G is Benign according to our data. Variant chr19-50909059-A-G is described in ClinVar as Benign. ClinVar VariationId is 1253084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	NM_004917.5	MANE Select	c.224+193T>C		intron	N/A	NP_004908.4
	KLK4	NM_001302961.2		c.-62+181T>C		intron	N/A	NP_001289890.1
	KLK4	NR_126566.2		n.217+181T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.224+193T>C		intron	N/A	ENSP00000326159.1	A0A0C4DFQ5
	KLK4	ENST00000431178.2	TSL:1	c.77+193T>C		intron	N/A	ENSP00000399448.2	Q9Y5K2-2
	KLK4	ENST00000596876.1	TSL:1	n.143+181T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77490 AN: 151664 Hom.: 20285 Cov.: 30

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.503

GnomAD4 exome AF: 0.525 AC: 696497 AN: 1326054 Hom.: 186073 Cov.: 40 AF XY: 0.524 AC XY: 338471 AN XY: 646428

African (AFR) AF: 0.486 AC: 14712 AN: 30294

American (AMR) AF: 0.517 AC: 15917 AN: 30800

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 11560 AN: 21168

East Asian (EAS) AF: 0.198 AC: 7005 AN: 35296

South Asian (SAS) AF: 0.429 AC: 29536 AN: 68886

European-Finnish (FIN) AF: 0.561 AC: 17934 AN: 31996

Middle Eastern (MID) AF: 0.549 AC: 2068 AN: 3764

European-Non Finnish (NFE) AF: 0.543 AC: 568964 AN: 1048612

Other (OTH) AF: 0.521 AC: 28801 AN: 55238

GnomAD4 genome AF: 0.511 AC: 77579 AN: 151782 Hom.: 20305 Cov.: 30 AF XY: 0.511 AC XY: 37915 AN XY: 74170

African (AFR) AF: 0.482 AC: 19939 AN: 41366

American (AMR) AF: 0.518 AC: 7913 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1851 AN: 3464

East Asian (EAS) AF: 0.220 AC: 1127 AN: 5134

South Asian (SAS) AF: 0.400 AC: 1924 AN: 4810

European-Finnish (FIN) AF: 0.567 AC: 5980 AN: 10556

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.548 AC: 37188 AN: 67878

Other (OTH) AF: 0.504 AC: 1062 AN: 2108

Alfa AF: 0.535 Hom.: 63993

Bravo AF: 0.507

Asia WGS AF: 0.317 AC: 1106 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.52
DANN	Benign	0.45
PhyloP100		-3.4
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2242670;

hg19: chr19-51412315;

COSMIC: COSV60676181;

COSMIC: COSV60676181;