rs1654552

Variant names:

• chr19-50909410-C-A
• rs1654552
• NM_004917.5:c.66G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004917.5(KLK4):​c.66G>T​(p.Ser22Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,613,460 control chromosomes in the GnomAD database, including 156,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11458 hom., cov: 32)
  • Exomes 𝑓: 0.44 (145226 hom.)
• Consequence: KLK4 NM_004917.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.425
• Publications: 17 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 -16 ACMG points.

• BP6: Variant 19-50909410-C-A is Benign according to our data. Variant chr19-50909410-C-A is described in ClinVar as Benign. ClinVar VariationId is 259565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.465 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.66G>T	p.Ser22Ser	synonymous	Exon 3 of 6	NP_004908.4
	KLK4	NM_001302961.2		c.-232G>T		5_prime_UTR	Exon 2 of 5	NP_001289890.1
	KLK4	NR_126566.2		n.62-15G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK4	ENST00000324041.6	TSL:1 MANE Select	c.66G>T	p.Ser22Ser	synonymous	Exon 3 of 6	ENSP00000326159.1	A0A0C4DFQ5
	KLK4	ENST00000602148.1	TSL:1	n.66G>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000472091.1	Q5BQA0
	KLK4	ENST00000598305.5	TSL:1	n.-217-15G>T		intron	N/A	ENSP00000469963.1	M0QYN5

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53261 AN: 151978 Hom.: 11460 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.452

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.400 AC: 100373 AN: 250952 AF XY: 0.402

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.463

Gnomad ASJ exome AF: 0.468

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.474

Gnomad NFE exome AF: 0.471

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.436 AC: 637077 AN: 1461364 Hom.: 145226 Cov.: 49 AF XY: 0.434 AC XY: 315690 AN XY: 726944

African (AFR) AF: 0.102 AC: 3422 AN: 33476

American (AMR) AF: 0.457 AC: 20441 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 12100 AN: 26134

East Asian (EAS) AF: 0.102 AC: 4036 AN: 39694

South Asian (SAS) AF: 0.313 AC: 27004 AN: 86246

European-Finnish (FIN) AF: 0.476 AC: 25424 AN: 53364

Middle Eastern (MID) AF: 0.410 AC: 2366 AN: 5768

European-Non Finnish (NFE) AF: 0.465 AC: 517288 AN: 1111588

Other (OTH) AF: 0.414 AC: 24996 AN: 60374

GnomAD4 genome AF: 0.350 AC: 53267 AN: 152096 Hom.: 11458 Cov.: 32 AF XY: 0.352 AC XY: 26177 AN XY: 74354

African (AFR) AF: 0.115 AC: 4780 AN: 41522

American (AMR) AF: 0.431 AC: 6587 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1559 AN: 3472

East Asian (EAS) AF: 0.112 AC: 579 AN: 5164

South Asian (SAS) AF: 0.292 AC: 1404 AN: 4816

European-Finnish (FIN) AF: 0.489 AC: 5157 AN: 10548

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31905 AN: 67976

Other (OTH) AF: 0.364 AC: 767 AN: 2106

Alfa AF: 0.415 Hom.: 13504

Bravo AF: 0.336

Asia WGS AF: 0.184 AC: 643 AN: 3478

EpiCase AF: 0.471

EpiControl AF: 0.470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.7
DANN	Benign	0.56
PhyloP100		-0.42
PromoterAI		-0.015	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1654552; hg19: chr19-51412666; COSMIC: COSV60675977; COSMIC: COSV60675977;