19-50907215-A-G

Variant names:

• chr19-50907215-A-G
• rs2235091
• NM_004917.5:c.613-129T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004917.5(KLK4):​c.613-129T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 933,878 control chromosomes in the GnomAD database, including 63,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (10907 hom., cov: 30)
  • Exomes 𝑓: 0.36 (52348 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.199
• Publications: 22 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-50907215-A-G is Benign according to our data. Variant chr19-50907215-A-G is described in ClinVar as Benign. ClinVar VariationId is 1261892.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 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.613-129T>C		intron	N/A	NP_004908.4
	KLK4	NM_001302961.2		c.328-129T>C		intron	N/A	NP_001289890.1
	KLK4	NR_126566.2		n.602-129T>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.613-129T>C		intron	N/A	ENSP00000326159.1
	KLK4	ENST00000431178.2	TSL:1	c.329-129T>C		intron	N/A	ENSP00000399448.2
	KLK4	ENST00000598305.5	TSL:1	n.*108-129T>C		intron	N/A	ENSP00000469963.1

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56831 AN: 151784 Hom.: 10894 Cov.: 30

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.359 AC: 280948 AN: 781976 Hom.: 52348 AF XY: 0.363 AC XY: 148597 AN XY: 409128

African (AFR) AF: 0.428 AC: 8485 AN: 19826

American (AMR) AF: 0.313 AC: 11028 AN: 35254

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 6967 AN: 21424

East Asian (EAS) AF: 0.179 AC: 5958 AN: 33364

South Asian (SAS) AF: 0.425 AC: 28596 AN: 67286

European-Finnish (FIN) AF: 0.345 AC: 14002 AN: 40618

Middle Eastern (MID) AF: 0.451 AC: 1306 AN: 2898

European-Non Finnish (NFE) AF: 0.365 AC: 190779 AN: 523290

Other (OTH) AF: 0.364 AC: 13827 AN: 38016

GnomAD4 genome AF: 0.374 AC: 56875 AN: 151902 Hom.: 10907 Cov.: 30 AF XY: 0.371 AC XY: 27524 AN XY: 74256

African (AFR) AF: 0.424 AC: 17545 AN: 41408

American (AMR) AF: 0.351 AC: 5355 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1188 AN: 3472

East Asian (EAS) AF: 0.174 AC: 901 AN: 5184

South Asian (SAS) AF: 0.419 AC: 2018 AN: 4816

European-Finnish (FIN) AF: 0.322 AC: 3390 AN: 10542

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.371 AC: 25202 AN: 67906

Other (OTH) AF: 0.388 AC: 817 AN: 2106

Alfa AF: 0.372 Hom.: 42549

Bravo AF: 0.377

Asia WGS AF: 0.306 AC: 1065 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.72
PhyloP100		-0.20
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

Other links and lift over

dbSNP: rs2235091; hg19: chr19-51410471;