19-50910650-A-T

Variant names:

• chr19-50910650-A-T
• rs2978642
• NM_004917.5:c.61+28T>A

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+28T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,547,322 control chromosomes in the GnomAD database, including 55,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9489 hom., cov: 31)
  • Exomes 𝑓: 0.25 (46291 hom.)
• Consequence: KLK4 NM_004917.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.895
• Publications: 13 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 19-50910650-A-T is Benign according to our data. Variant chr19-50910650-A-T is described in ClinVar as Benign. ClinVar VariationId is 1286882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.61+28T>A		intron_variant	Intron 2 of 5	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.-237+28T>A		intron_variant	Intron 1 of 4		NP_001289890.1
KLK4	NR_126566.2	n.61+28T>A		intron_variant	Intron 1 of 4
KLK4	XM_011527545.4	c.61+28T>A		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+28T>A		intron_variant	Intron 2 of 5	1	NM_004917.5	ENSP00000326159.1
KLK4	ENST00000598305.5	n.-218+28T>A		intron_variant	Intron 1 of 4	1		ENSP00000469963.1
KLK4	ENST00000602148.1	n.61+28T>A		intron_variant	Intron 1 of 4	1		ENSP00000472091.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49488 AN: 151832 Hom.: 9462 Cov.: 31

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.266 AC: 42385 AN: 159112 AF XY: 0.266

Gnomad AFR exome AF: 0.543

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.251 AC: 349958 AN: 1395372 Hom.: 46291 Cov.: 30 AF XY: 0.253 AC XY: 173964 AN XY: 688692

African (AFR) AF: 0.549 AC: 17329 AN: 31580

American (AMR) AF: 0.228 AC: 8154 AN: 35754

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5457 AN: 25170

East Asian (EAS) AF: 0.216 AC: 7756 AN: 35850

South Asian (SAS) AF: 0.330 AC: 26159 AN: 79196

European-Finnish (FIN) AF: 0.219 AC: 10803 AN: 49414

Middle Eastern (MID) AF: 0.334 AC: 1899 AN: 5686

European-Non Finnish (NFE) AF: 0.239 AC: 256782 AN: 1074808

Other (OTH) AF: 0.270 AC: 15619 AN: 57914

GnomAD4 genome AF: 0.326 AC: 49561 AN: 151950 Hom.: 9489 Cov.: 31 AF XY: 0.322 AC XY: 23929 AN XY: 74258

African (AFR) AF: 0.540 AC: 22368 AN: 41404

American (AMR) AF: 0.262 AC: 3991 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1198 AN: 5150

South Asian (SAS) AF: 0.323 AC: 1554 AN: 4814

European-Finnish (FIN) AF: 0.206 AC: 2179 AN: 10586

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16433 AN: 67964

Other (OTH) AF: 0.326 AC: 686 AN: 2102

Alfa AF: 0.201 Hom.: 652

Bravo AF: 0.337

Asia WGS AF: 0.291 AC: 1013 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	0.83
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2978642; hg19: chr19-51413906; COSMIC: COSV107402145; COSMIC: COSV107402145;