19-50948701-G-T

Variant names:

• chr19-50948701-G-T
• rs758457993
• NM_012427.5:c.665C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012427.5(KLK5):​c.665C>A​(p.Pro222Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P222L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• Publications: 2 publications found

Genes affected

KLK5 (HGNC:6366): (kallikrein related peptidase 5) 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. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012427.5. 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
	KLK5	NM_012427.5	MANE Select	c.665C>A	p.Pro222Gln	missense	Exon 5 of 6	NP_036559.1	Q9Y337
	KLK5	NM_001077491.2		c.665C>A	p.Pro222Gln	missense	Exon 6 of 7	NP_001070959.1	Q9Y337
	KLK5	NM_001077492.2		c.665C>A	p.Pro222Gln	missense	Exon 5 of 6	NP_001070960.1	Q9Y337

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK5	ENST00000336334.8	TSL:1 MANE Select	c.665C>A	p.Pro222Gln	missense	Exon 5 of 6	ENSP00000337733.2	Q9Y337
	KLK5	ENST00000391809.6	TSL:1	c.665C>A	p.Pro222Gln	missense	Exon 6 of 7	ENSP00000375685.1	Q9Y337
	KLK5	ENST00000593428.5	TSL:1	c.665C>A	p.Pro222Gln	missense	Exon 5 of 6	ENSP00000471966.1	Q9Y337

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.012	D
Polyphen		0.97	D
Vest4		0.54
MutPred		0.58		Gain of helix (P = 0.1736)
MVP		0.99
MPC		0.10
ClinPred		0.96	D
GERP RS		4.5
Varity_R		0.32
gMVP		0.65
Mutation Taster		=72/28	polymorphism

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: rs758457993; hg19: chr19-51451957;