19-50943710-C-T

Variant names:

• chr19-50943710-C-T
• rs146723372
• NM_012427.5:c.803G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_012427.5(KLK5):​c.803G>A​(p.Arg268Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.36
• Publications: 1 publications found

Genes affected

KLK5 (HGNC:6366): (kallikrein related peptidase 5) Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis and some have potential as novel cancer and other disease biomarkers. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. The encoded protein is secreted and may be involved in desquamation in the epidermis. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012279451).
• BP6: Variant 19-50943710-C-T is Benign according to our data. Variant chr19-50943710-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2595156.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012427.5. 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
	KLK5	NM_012427.5	MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 6 of 6	NP_036559.1	Q9Y337
	KLK5	NM_001077491.2		c.803G>A	p.Arg268Gln	missense	Exon 7 of 7	NP_001070959.1	Q9Y337
	KLK5	NM_001077492.2		c.803G>A	p.Arg268Gln	missense	Exon 6 of 6	NP_001070960.1	Q9Y337

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLK5	ENST00000336334.8	TSL:1 MANE Select	c.803G>A	p.Arg268Gln	missense	Exon 6 of 6	ENSP00000337733.2	Q9Y337
	KLK5	ENST00000391809.6	TSL:1	c.803G>A	p.Arg268Gln	missense	Exon 7 of 7	ENSP00000375685.1	Q9Y337
	KLK5	ENST00000593428.5	TSL:1	c.803G>A	p.Arg268Gln	missense	Exon 6 of 6	ENSP00000471966.1	Q9Y337

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151928 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251304 AF XY: 0.0000221

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461808 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 727206

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111952

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152046 Hom.: 0 Cov.: 31 AF XY: 0.000283 AC XY: 21 AN XY: 74314

African (AFR) AF: 0.000796 AC: 33 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.0000713 Hom.: 0

Bravo AF: 0.000193

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.062
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.58
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.015	N
PhyloP100		1.4
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.092
MVP		0.57
MPC		0.11
ClinPred		0.0079	T
GERP RS		1.7
Varity_R		0.17
gMVP		0.38
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146723372; hg19: chr19-51446966; COSMIC: COSV60451006;