19-50977569-C-G

Variant names:

• chr19-50977569-C-G
• NM_005046.4:c.729G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005046.4(KLK7):​c.729G>C​(p.Lys243Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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: 32)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.99

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121848226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK7	NM_005046.4	c.729G>C	p.Lys243Asn	missense_variant	Exon 6 of 6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.729G>C	p.Lys243Asn	missense_variant	Exon 6 of 6		NP_644806.1
KLK7	NM_001243126.1	c.708G>C	p.Lys236Asn	missense_variant	Exon 5 of 5		NP_001230055.1
KLK7	NM_001207053.2	c.513G>C	p.Lys171Asn	missense_variant	Exon 5 of 5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.729G>C	p.Lys243Asn	missense_variant	Exon 6 of 6	1	NM_005046.4	ENSP00000470538.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.729G>C (p.K243N) alteration is located in exon 6 (coding exon 5) of the KLK7 gene. This alteration results from a G to C substitution at nucleotide position 729, causing the lysine (K) at amino acid position 243 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.033
DANN	Benign	0.86
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.032	T;.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.45	N;N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.36	N;.;.
REVEL	Benign	0.056
Sift	Benign	0.36	T;.;.
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.074
MutPred		0.47		Loss of methylation at K243 (P = 0.0012);Loss of methylation at K243 (P = 0.0012);.;
MVP		0.62
MPC		0.035
ClinPred		0.16	T
GERP RS		-9.8
Varity_R		0.14
gMVP		0.63

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51480825;