rs2979451

Variant names:

• chr19-50908132-T-C
• rs2979451
• ENST00000596876.1:n.841A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000596876.1(KLK4):​n.841A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 596,418 control chromosomes in the GnomAD database, including 32,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11705 hom., cov: 31)
  • Exomes 𝑓: 0.30 (21129 hom.)
• Consequence: KLK4 ENST00000596876.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.39
• Publications: 5 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=-0.88).
• BP6: Variant 19-50908132-T-C is Benign according to our data. Variant chr19-50908132-T-C is described in ClinVar as Benign. ClinVar VariationId is 1279596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.612+227A>G		intron_variant	Intron 5 of 5	ENST00000324041.6	NP_004908.4
KLK4	NM_001302961.2	c.327+227A>G		intron_variant	Intron 4 of 4		NP_001289890.1
KLK4	NR_126566.2	n.601+227A>G		intron_variant	Intron 4 of 4
KLK4	XM_011527545.4	c.*334A>G		downstream_gene_variant			XP_011525847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.612+227A>G		intron_variant	Intron 5 of 5	1	NM_004917.5	ENSP00000326159.1

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55999 AN: 151890 Hom.: 11672 Cov.: 31

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.301 AC: 133832 AN: 444410 Hom.: 21129 Cov.: 5 AF XY: 0.300 AC XY: 70110 AN XY: 233816

African (AFR) AF: 0.571 AC: 7185 AN: 12578

American (AMR) AF: 0.258 AC: 5375 AN: 20818

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 3674 AN: 13490

East Asian (EAS) AF: 0.168 AC: 4765 AN: 28382

South Asian (SAS) AF: 0.284 AC: 13138 AN: 46186

European-Finnish (FIN) AF: 0.316 AC: 8389 AN: 26540

Middle Eastern (MID) AF: 0.397 AC: 763 AN: 1920

European-Non Finnish (NFE) AF: 0.306 AC: 82458 AN: 269422

Other (OTH) AF: 0.322 AC: 8085 AN: 25074

GnomAD4 genome AF: 0.369 AC: 56076 AN: 152008 Hom.: 11705 Cov.: 31 AF XY: 0.363 AC XY: 26992 AN XY: 74320

African (AFR) AF: 0.569 AC: 23584 AN: 41418

American (AMR) AF: 0.299 AC: 4564 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 1009 AN: 3472

East Asian (EAS) AF: 0.151 AC: 780 AN: 5178

South Asian (SAS) AF: 0.276 AC: 1333 AN: 4824

European-Finnish (FIN) AF: 0.287 AC: 3039 AN: 10580

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20592 AN: 67958

Other (OTH) AF: 0.385 AC: 812 AN: 2110

Alfa AF: 0.315 Hom.: 7397

Bravo AF: 0.378

Asia WGS AF: 0.236 AC: 823 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

- -

Jun 19, 2021

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	-0.88
CADD	Benign	3.3
DANN	Benign	0.68
PhyloP100		1.4
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: rs2979451; hg19: chr19-51411388;