19-50977573-G-A

Position:

• chr19-50977573-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK7	NM_005046.4	c.725C>T	p.Thr242Ile	missense_variant	6/6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.725C>T	p.Thr242Ile	missense_variant	6/6		NP_644806.1
KLK7	NM_001243126.1	c.704C>T	p.Thr235Ile	missense_variant	5/5		NP_001230055.1
KLK7	NM_001207053.2	c.509C>T	p.Thr170Ile	missense_variant	5/5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.725C>T	p.Thr242Ile	missense_variant	6/6	1	NM_005046.4	ENSP00000470538	P1
	ENST00000594512.1	n.297+4240G>A		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes AF: 0.00216 AC: 544 AN: 251398 Hom.: 9 AF XY: 0.00162 AC XY: 220 AN XY: 135882

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 SAS exome AF: 0.000229

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

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.00210

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

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00243 Hom.: 5

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.069	T;.;T
MetaRNN	Benign	0.0026	T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	-0.29	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.83	N;.;.
REVEL	Benign	0.18
Sift	Benign	0.091	T;.;.
Sift4G	Benign	0.47	T;T;T
Polyphen		0.017	B;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

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

LitVar

Other links and lift over

dbSNP: rs112736390; hg19: chr19-51480829;