19-50948960-C-T

Variant names:

• chr19-50948960-C-T
• rs200140569
• NM_012427.5:c.491G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_012427.5(KLK5):​c.491G>A​(p.Arg164His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.649

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108192295).
• BP6: Variant 19-50948960-C-T is Benign according to our data. Variant chr19-50948960-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2356852.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK5	NM_012427.5	c.491G>A	p.Arg164His	missense_variant	Exon 4 of 6	ENST00000336334.8	NP_036559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK5	ENST00000336334.8	c.491G>A	p.Arg164His	missense_variant	Exon 4 of 6	1	NM_012427.5	ENSP00000337733.2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151942 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000143 AC: 36 AN: 251462 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000220 AC: 322 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.000221 AC XY: 161 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000268

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152060 Hom.: 0 Cov.: 30 AF XY: 0.0000942 AC XY: 7 AN XY: 74308

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000269 Hom.: 2

Bravo AF: 0.000102

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 20, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.1
DANN	Benign	0.67
DEOGEN2	Uncertain	0.48	T;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.48	.;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L;L;L;.
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.4	N;N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.58	T;T;.;.
Sift4G	Benign	0.43	T;T;T;.
Polyphen		0.99	D;D;D;.
Vest4		0.088
MVP		0.84
MPC		0.12
ClinPred		0.10	T
GERP RS		-7.7
Varity_R		0.13
gMVP		0.34

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: rs200140569; hg19: chr19-51452216; COSMIC: COSV60450961; COSMIC: COSV60450961;