19-51006650-C-A

Variant names:

• chr19-51006650-C-A
• NM_012315.2:c.274G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012315.2(KLK9):​c.274G>T​(p.Asp92Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KLK9 NM_012315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0680

Genes affected

KLK9 (HGNC:6370): (kallikrein related peptidase 9) The protein encoded by this gene is a kallikrein-related serine protease. This gene is activated by steroid hormones in a human breast cancer cell line, making it a good marker for cancer detection. The encoded protein is found primarily in the cytoplasm.[provided by RefSeq, Oct 2010]

ENSG00000269741 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16006619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK9	NM_012315.2	c.274G>T	p.Asp92Tyr	missense_variant	Exon 3 of 5	ENST00000594211.2	NP_036447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK9	ENST00000594211.2	c.274G>T	p.Asp92Tyr	missense_variant	Exon 3 of 5	1	NM_012315.2	ENSP00000469417.1
ENSG00000269741	ENST00000250366.6	n.274G>T		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000250366.5
KLK9	ENST00000544410.1	n.117G>T		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000443289.1
ENSG00000267879	ENST00000594512.1	n.430-5373C>A		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.274G>T (p.D92Y) alteration is located in exon 3 (coding exon 3) of the KLK9 gene. This alteration results from a G to T substitution at nucleotide position 274, causing the aspartic acid (D) at amino acid position 92 to be replaced by a tyrosine (Y). 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	0.35
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Benign	0.79
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.041	N
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.47	N
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.55	T
Polyphen		0.18	B
Vest4		0.27
MutPred		0.57		Gain of catalytic residue at L87 (P = 0.0876);
MVP		0.83
ClinPred		0.39	T
GERP RS		1.8
Varity_R		0.065
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-51509906;