19-50977573-G-A

Variant names:

• chr19-50977573-G-A
• rs112736390
• NM_005046.4:c.725C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005046.4(KLK7):​c.725C>T​(p.Thr242Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,960 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (13 hom.)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.33
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002581507).
• BP6: Variant 19-50977573-G-A is Benign according to our data. Variant chr19-50977573-G-A is described in ClinVar as Benign. ClinVar VariationId is 775422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00792 (1206/152254) while in subpopulation AFR AF = 0.0274 (1140/41532). AF 95% confidence interval is 0.0261. There are 17 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.725C>T	p.Thr242Ile	missense	Exon 6 of 6	NP_005037.1	P49862-1
	KLK7	NM_139277.2		c.725C>T	p.Thr242Ile	missense	Exon 6 of 6	NP_644806.1	P49862-1
	KLK7	NM_001243126.1		c.704C>T	p.Thr235Ile	missense	Exon 5 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.725C>T	p.Thr242Ile	missense	Exon 6 of 6	ENSP00000470538.1	P49862-1
	KLK7	ENST00000597707.5	TSL:1	c.509C>T	p.Thr170Ile	missense	Exon 5 of 5	ENSP00000469950.1	P49862-2
	KLK7	ENST00000391807.5	TSL:5	c.725C>T	p.Thr242Ile	missense	Exon 6 of 6	ENSP00000375683.1	P49862-1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152136 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00216 AC: 544 AN: 251398 AF XY: 0.00162

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000787 AC: 1150 AN: 1461706 Hom.: 13 Cov.: 31 AF XY: 0.000681 AC XY: 495 AN XY: 727138

African (AFR) AF: 0.0260 AC: 871 AN: 33472

American (AMR) AF: 0.00181 AC: 81 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111954

Other (OTH) AF: 0.00210 AC: 127 AN: 60386

GnomAD4 genome AF: 0.00792 AC: 1206 AN: 152254 Hom.: 17 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74460

African (AFR) AF: 0.0274 AC: 1140 AN: 41532

American (AMR) AF: 0.00294 AC: 45 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68018

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00413 Hom.: 13

Bravo AF: 0.00889

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00275 AC: 334

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.0
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.069	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-2.3
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.18
Sift	Benign	0.091	T
Sift4G	Benign	0.47	T
Polyphen		0.017	B
Vest4		0.12
MVP		0.84
MPC		0.033
ClinPred		0.0020	T
GERP RS		-3.0
Varity_R		0.13
gMVP		0.67
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: rs112736390; hg19: chr19-51480829;