chr19-50980268-G-A

Position:

• chr19-50980268-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005046.4(KLK7):​c.441C>T​(p.Ser147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,613,952 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0018 (14 hom.)
• Consequence: KLK7 NM_005046.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.30

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 19-50980268-G-A is Benign according to our data. Variant chr19-50980268-G-A is described in ClinVar as [Benign]. Clinvar id is 771933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00178 (2607/1461762) while in subpopulation MID AF= 0.0199 (115/5768). AF 95% confidence interval is 0.017. There are 14 homozygotes in gnomad4_exome. There are 1313 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK7	NM_005046.4	c.441C>T	p.Ser147=	synonymous_variant	4/6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.441C>T	p.Ser147=	synonymous_variant	4/6		NP_644806.1
KLK7	NM_001243126.1	c.420C>T	p.Ser140=	synonymous_variant	3/5		NP_001230055.1
KLK7	NM_001207053.2	c.225C>T	p.Ser75=	synonymous_variant	3/5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.441C>T	p.Ser147=	synonymous_variant	4/6	1	NM_005046.4	ENSP00000470538	P1
	ENST00000594512.1	n.297+6935G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152072 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00239 AC: 599 AN: 250990 Hom.: 0 AF XY: 0.00246 AC XY: 334 AN XY: 135734

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00845

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00178 AC: 2607 AN: 1461762 Hom.: 14 Cov.: 33 AF XY: 0.00181 AC XY: 1313 AN XY: 727192

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00148

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152190 Hom.: 0 Cov.: 29 AF XY: 0.00167 AC XY: 124 AN XY: 74418

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00166

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00229 Hom.: 0

Bravo AF: 0.00176

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00350

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.2
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs147827338; hg19: chr19-51483524; COSMIC: COSV58343826; COSMIC: COSV58343826;