9-128151969-T-C

Position:

• chr9-128151969-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000277480.7(LCN2):​c.419T>C​(p.Met140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,461,804 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: LCN2 ENST00000277480.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.388

Genes affected

LCN2 (HGNC:6526): (lipocalin 2) This gene encodes a protein that belongs to the lipocalin family. Members of this family transport small hydrophobic molecules such as lipids, steroid hormones and retinoids. The protein encoded by this gene is a neutrophil gelatinase-associated lipocalin and plays a role in innate immunity by limiting bacterial growth as a result of sequestering iron-containing siderophores. The presence of this protein in blood and urine is an early biomarker of acute kidney injury. This protein is thought to be be involved in multiple cellular processes, including maintenance of skin homeostasis, and suppression of invasiveness and metastasis. Mice lacking this gene are more susceptible to bacterial infection than wild type mice. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28301054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCN2	NM_005564.5	c.419T>C	p.Met140Thr	missense_variant	4/7	ENST00000277480.7	NP_005555.2
LCN2	XM_047423376.1	c.419T>C	p.Met140Thr	missense_variant	4/6		XP_047279332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCN2	ENST00000277480.7	c.419T>C	p.Met140Thr	missense_variant	4/7	1	NM_005564.5	ENSP00000277480	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461804 Hom.: 0 Cov.: 36 AF XY: 0.0000110 AC XY: 8 AN XY: 727206

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: 0.0000171

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.419T>C (p.M140T) alteration is located in exon 4 (coding exon 4) of the LCN2 gene. This alteration results from a T to C substitution at nucleotide position 419, causing the methionine (M) at amino acid position 140 to be replaced by a threonine (T). 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	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.2
DANN	Benign	0.38
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.51	.;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	0.96	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.040
Sift	Benign	0.13	T;T;T
Sift4G	Uncertain	0.018	D;D;D
Polyphen		0.14	B;B;.
Vest4		0.41
MutPred		0.71		Loss of stability (P = 0.0564);Loss of stability (P = 0.0564);.;
MVP		0.061
MPC		0.037
ClinPred		0.050	T
GERP RS		0.23
Varity_R		0.46
gMVP		0.57

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: rs1835012122; hg19: chr9-130914248;