19-50948689-T-C

Variant names:

• chr19-50948689-T-C
• NM_012427.5:c.677A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012427.5(KLK5):​c.677A>G​(p.Asp226Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: KLK5 NM_012427.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK5	NM_012427.5	c.677A>G	p.Asp226Gly	missense_variant	Exon 5 of 6	ENST00000336334.8	NP_036559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK5	ENST00000336334.8	c.677A>G	p.Asp226Gly	missense_variant	Exon 5 of 6	1	NM_012427.5	ENSP00000337733.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.677A>G (p.D226G) alteration is located in exon 5 (coding exon 4) of the KLK5 gene. This alteration results from a A to G substitution at nucleotide position 677, causing the aspartic acid (D) at amino acid position 226 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	.;.;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.030	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.45
Sift	Benign	0.60	T;T;.
Sift4G	Benign	0.61	T;T;T
Polyphen		0.79	P;P;P
Vest4		0.39
MutPred		0.61		Loss of stability (P = 0.043);Loss of stability (P = 0.043);Loss of stability (P = 0.043);
MVP		0.93
MPC		0.14
ClinPred		0.38	T
GERP RS		2.5
Varity_R		0.25
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51451945;