19-50943777-C-G

Variant names:

• chr19-50943777-C-G
• rs753623477
• NM_012427.5:c.736G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012427.5(KLK5):​c.736G>C​(p.Gly246Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

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.736G>C	p.Gly246Arg	missense	Exon 6 of 6	NP_036559.1	Q9Y337
	KLK5	NM_001077491.2		c.736G>C	p.Gly246Arg	missense	Exon 7 of 7	NP_001070959.1	Q9Y337
	KLK5	NM_001077492.2		c.736G>C	p.Gly246Arg	missense	Exon 6 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.736G>C	p.Gly246Arg	missense	Exon 6 of 6	ENSP00000337733.2	Q9Y337
	KLK5	ENST00000391809.6	TSL:1	c.736G>C	p.Gly246Arg	missense	Exon 7 of 7	ENSP00000375685.1	Q9Y337
	KLK5	ENST00000593428.5	TSL:1	c.736G>C	p.Gly246Arg	missense	Exon 6 of 6	ENSP00000471966.1	Q9Y337

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.93		Loss of glycosylation at S245 (P = 0.0505)
MVP		1.0
MPC		0.55
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.83
gMVP		0.95
Mutation Taster		=64/36	polymorphism

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: rs753623477; hg19: chr19-51447033;