rs751782967

Variant names:

• chr19-50949964-G-A
• rs751782967
• NM_012427.5:c.226C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012427.5(KLK5):​c.226C>T​(p.His76Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.558
• 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]

ENSG00000269495 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33404118).

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.226C>T	p.His76Tyr	missense	Exon 3 of 6	NP_036559.1	Q9Y337
	KLK5	NM_001077491.2		c.226C>T	p.His76Tyr	missense	Exon 4 of 7	NP_001070959.1	Q9Y337
	KLK5	NM_001077492.2		c.226C>T	p.His76Tyr	missense	Exon 3 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.226C>T	p.His76Tyr	missense	Exon 3 of 6	ENSP00000337733.2	Q9Y337
	KLK5	ENST00000391809.6	TSL:1	c.226C>T	p.His76Tyr	missense	Exon 4 of 7	ENSP00000375685.1	Q9Y337
	KLK5	ENST00000593428.5	TSL:1	c.226C>T	p.His76Tyr	missense	Exon 3 of 6	ENSP00000471966.1	Q9Y337

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250260 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461706 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	8.8
DANN	Benign	0.97
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.56
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.25
Sift	Benign	0.041	D
Sift4G	Uncertain	0.042	D
Polyphen		0.11	B
Vest4		0.21
MutPred		0.64		Loss of solvent accessibility (P = 0.0062)
MVP		0.59
MPC		0.16
ClinPred		0.083	T
GERP RS		-5.2
Varity_R		0.13
gMVP		0.56
Mutation Taster		=99/1	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: rs751782967; hg19: chr19-51453220;