chr19-50943714-C-T

Variant names:

• chr19-50943714-C-T
• rs61729816
• NM_012427.5:c.799G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012427.5(KLK5):​c.799G>A​(p.Ala267Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A267S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK5	NM_012427.5	c.799G>A	p.Ala267Thr	missense_variant	Exon 6 of 6	ENST00000336334.8	NP_036559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK5	ENST00000336334.8	c.799G>A	p.Ala267Thr	missense_variant	Exon 6 of 6	1	NM_012427.5	ENSP00000337733.2
KLK5	ENST00000391809.6	c.799G>A	p.Ala267Thr	missense_variant	Exon 7 of 7	1		ENSP00000375685.1
KLK5	ENST00000593428.5	c.799G>A	p.Ala267Thr	missense_variant	Exon 6 of 6	1		ENSP00000471966.1
KLK5	ENST00000595585.1	n.895G>A		non_coding_transcript_exon_variant	Exon 4 of 4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727148

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D;D;.
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.98	D;D;D
Vest4		0.28
MutPred		0.79		Gain of phosphorylation at A267 (P = 0.0652);Gain of phosphorylation at A267 (P = 0.0652);Gain of phosphorylation at A267 (P = 0.0652);
MVP		0.99
MPC		0.30
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.48
gMVP		0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs61729816; hg19: chr19-51446970; COSMIC: COSV60450575;