19-51006613-C-T

Variant names:

• chr19-51006613-C-T
• rs775415538
• NM_012315.2:c.311G>A

Variant summary

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

The NM_012315.2(KLK9):​c.311G>A​(p.Ser104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KLK9 NM_012315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.683

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=0.093523234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK9	NM_012315.2	c.311G>A	p.Ser104Asn	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.311G>A	p.Ser104Asn	missense_variant	Exon 3 of 5	1	NM_012315.2	ENSP00000469417.1
ENSG00000269741	ENST00000250366.6	n.311G>A		non_coding_transcript_exon_variant	Exon 3 of 7	2		ENSP00000250366.5
KLK9	ENST00000544410.1	n.154G>A		non_coding_transcript_exon_variant	Exon 2 of 4	2		ENSP00000443289.1
ENSG00000267879	ENST00000594512.1	n.430-5410C>T		intron_variant	Intron 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461282 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726958

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.311G>A (p.S104N) alteration is located in exon 3 (coding exon 3) of the KLK9 gene. This alteration results from a G to A substitution at nucleotide position 311, causing the serine (S) at amino acid position 104 to be replaced by an asparagine (N). 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	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.9
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.040	N
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.47	N
PrimateAI	Benign	0.47	T
Sift4G	Benign	0.47	T
Polyphen		0.056	B
Vest4		0.18
MutPred		0.36		Loss of disorder (P = 0.1692);
MVP		0.78
ClinPred		0.057	T
GERP RS		1.9
Varity_R		0.040
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs775415538; hg19: chr19-51509869;