19-50859048-C-G

Variant names:

• chr19-50859048-C-G
• rs11084034
• NM_001648.2:c.630+453C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001648.2(KLK3):​c.630+453C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 75,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: KLK3 NM_001648.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.89
• Publications: 3 publications found

Genes affected

KLK3 (HGNC:6364): (kallikrein related peptidase 3) 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. The gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. It encodes a single-chain glycoprotein, a protease which is synthesized in the epithelial cells of the prostate gland, and is present in seminal plasma. It is thought to function normally in the liquefaction of seminal coagulum, presumably by hydrolysis of the high molecular mass seminal vesicle protein. The serum level of this protein, called PSA in the clinical setting, is useful in the diagnosis and monitoring of prostatic carcinoma. Alternate splicing of this gene generates several transcript variants encoding different isoforms. [provided by RefSeq, Dec 2019]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK3	NM_001648.2	c.630+453C>G		intron_variant	Intron 4 of 4	ENST00000326003.7	NP_001639.1
KLK3	NM_001030047.1	c.630+453C>G		intron_variant	Intron 4 of 4		NP_001025218.1
KLK3	NM_001030048.1	c.501+453C>G		intron_variant	Intron 4 of 4		NP_001025219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK3	ENST00000326003.7	c.630+453C>G		intron_variant	Intron 4 of 4	1	NM_001648.2	ENSP00000314151.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000132 AC: 1 AN: 75960 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 38622

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 3004

American (AMR) AF: 0.00 AC: 0 AN: 4068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2682

East Asian (EAS) AF: 0.00 AC: 0 AN: 5670

South Asian (SAS) AF: 0.00 AC: 0 AN: 2970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 48602

Other (OTH) AF: 0.000207 AC: 1 AN: 4830

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 1254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.12
DANN	Benign	0.46
PhyloP100		-2.9

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: rs11084034; hg19: chr19-51362304;