rs1654551

Variant names:

• chr19-50909412-A-C
• rs1654551
• NM_004917.5:c.64T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_004917.5(KLK4):​c.64T>G​(p.Ser22Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0847 in 1,613,798 control chromosomes in the GnomAD database, including 6,967 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S22W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.12 (1464 hom., cov: 31)
  • Exomes 𝑓: 0.081 (5503 hom.)
• Consequence: KLK4 NM_004917.5 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 18 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.031208 (below the threshold of 3.09). Trascript score misZ: -0.079907 (below the threshold of 3.09). GenCC associations: The gene is linked to amelogenesis imperfecta type 2, amelogenesis imperfecta type 2A1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026489794).
• BP6: Variant 19-50909412-A-C is Benign according to our data. Variant chr19-50909412-A-C is described in ClinVar as Benign. ClinVar VariationId is 1258657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK4	NM_004917.5	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000324041.6	NP_004908.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK4	ENST00000324041.6	c.64T>G	p.Ser22Ala	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_004917.5	ENSP00000326159.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 18000 AN: 152060 Hom.: 1456 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.0220

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0622

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0792

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0744

Gnomad OTH AF: 0.0943

GnomAD2 exomes AF: 0.0881 AC: 22104 AN: 250912 AF XY: 0.0889

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0568

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.0833

Gnomad NFE exome AF: 0.0743

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0812 AC: 118722 AN: 1461620 Hom.: 5503 Cov.: 36 AF XY: 0.0819 AC XY: 59582 AN XY: 727086

African (AFR) AF: 0.246 AC: 8225 AN: 33474

American (AMR) AF: 0.0470 AC: 2103 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 1520 AN: 26132

East Asian (EAS) AF: 0.0996 AC: 3953 AN: 39694

South Asian (SAS) AF: 0.113 AC: 9762 AN: 86254

European-Finnish (FIN) AF: 0.0833 AC: 4442 AN: 53356

Middle Eastern (MID) AF: 0.0858 AC: 495 AN: 5768

European-Non Finnish (NFE) AF: 0.0743 AC: 82662 AN: 1111838

Other (OTH) AF: 0.0921 AC: 5560 AN: 60380

GnomAD4 genome AF: 0.119 AC: 18046 AN: 152178 Hom.: 1464 Cov.: 31 AF XY: 0.118 AC XY: 8779 AN XY: 74402

African (AFR) AF: 0.233 AC: 9662 AN: 41510

American (AMR) AF: 0.0651 AC: 996 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 216 AN: 3472

East Asian (EAS) AF: 0.104 AC: 535 AN: 5154

South Asian (SAS) AF: 0.104 AC: 502 AN: 4826

European-Finnish (FIN) AF: 0.0792 AC: 839 AN: 10598

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0743 AC: 5056 AN: 68014

Other (OTH) AF: 0.0943 AC: 199 AN: 2110

Alfa AF: 0.0931 Hom.: 484

Bravo AF: 0.124

TwinsUK AF: 0.0804 AC: 298

ALSPAC AF: 0.0698 AC: 269

ESP6500AA AF: 0.212 AC: 933

ESP6500EA AF: 0.0716 AC: 616

ExAC AF: 0.0922 AC: 11194

Asia WGS AF: 0.0990 AC: 344 AN: 3478

EpiCase AF: 0.0709

EpiControl AF: 0.0735

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22970239) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	3.9
DANN	Benign	0.50
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.92	T
PhyloP100		-1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.18
Sift	Benign	0.76	T
Sift4G	Benign	0.91	T
Vest4		0.028
MPC		0.28
ClinPred		0.0088	T
GERP RS		-7.0
PromoterAI		-0.026	Neutral
gMVP		0.48
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1654551; hg19: chr19-51412668; COSMIC: COSV60675801; COSMIC: COSV60675801;