chr19-50979901-A-T

Variant names:

• chr19-50979901-A-T
• NM_005046.4:c.493T>A

Variant summary

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

The NM_005046.4(KLK7):​c.493T>A​(p.Cys165Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07
• Publications: 0 publications found

Genes affected

KLK7 (HGNC:6368): (kallikrein related peptidase 7) This gene encodes a member of the kallikrein subfamily of serine proteases. These enzymes have diverse physiological functions and many kallikrein genes are biomarkers for cancer. The encoded protein has chymotrypsin-like activity and plays a role in the proteolysis of intercellular cohesive structures that precedes desquamation, the shedding of the outermost layer of the epidermis. The encoded protein may play a role in cancer invasion and metastasis, and increased expression of this gene is associated with unfavorable prognosis and progression of several types of cancer. Polymorphisms in this gene may play a role in the development of atopic dermatitis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, which is one of fifteen kallikrein subfamily members located in a gene cluster on chromosome 19. [provided by RefSeq, May 2011]

ENSG00000267879 (HGNC:):

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, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005046.4. 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
	KLK7	NM_005046.4	MANE Select	c.493T>A	p.Cys165Ser	missense	Exon 5 of 6	NP_005037.1	P49862-1
	KLK7	NM_139277.2		c.493T>A	p.Cys165Ser	missense	Exon 5 of 6	NP_644806.1	P49862-1
	KLK7	NM_001243126.1		c.472T>A	p.Cys158Ser	missense	Exon 4 of 5	NP_001230055.1	P49862

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK7	ENST00000595820.6	TSL:1 MANE Select	c.493T>A	p.Cys165Ser	missense	Exon 5 of 6	ENSP00000470538.1	P49862-1
	KLK7	ENST00000597707.5	TSL:1	c.277T>A	p.Cys93Ser	missense	Exon 4 of 5	ENSP00000469950.1	P49862-2
	KLK7	ENST00000391807.5	TSL:5	c.493T>A	p.Cys165Ser	missense	Exon 5 of 6	ENSP00000375683.1	P49862-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.74	N
PhyloP100		4.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.80		Gain of disorder (P = 0.0176)
MVP		0.88
MPC		0.26
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.89
gMVP		0.72
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr19-51483157;