rs916567941

Variant names:

• chr19-50979867-C-G
• rs916567941
• NM_005046.4:c.527G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-50979867-C-G
• chr19-50979867-C-T

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.527G>C​(p.Cys176Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000378 in 1,589,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95
• 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, 0.992

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.527G>C	p.Cys176Ser	missense	Exon 5 of 6	NP_005037.1	P49862-1
	KLK7	NM_139277.2		c.527G>C	p.Cys176Ser	missense	Exon 5 of 6	NP_644806.1	P49862-1
	KLK7	NM_001243126.1		c.506G>C	p.Cys169Ser	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.527G>C	p.Cys176Ser	missense	Exon 5 of 6	ENSP00000470538.1	P49862-1
	KLK7	ENST00000597707.5	TSL:1	c.311G>C	p.Cys104Ser	missense	Exon 4 of 5	ENSP00000469950.1	P49862-2
	KLK7	ENST00000391807.5	TSL:5	c.527G>C	p.Cys176Ser	missense	Exon 5 of 6	ENSP00000375683.1	P49862-1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436946 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 711962

African (AFR) AF: 0.0000302 AC: 1 AN: 33144

American (AMR) AF: 0.00 AC: 0 AN: 40614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 38890

South Asian (SAS) AF: 0.00 AC: 0 AN: 82106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099512

Other (OTH) AF: 0.00 AC: 0 AN: 59606

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.0000966 AC: 4 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

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	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.86		Gain of disorder (P = 0.0083)
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.97
Mutation Taster		=51/49	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: rs916567941; hg19: chr19-51483123;