9-136757045-A-T

Position:

• chr9-136757045-A-T

Variant summary

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

The ENST00000371688.8(LCN8):​c.148T>A​(p.Tyr50Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,460,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: LCN8 ENST00000371688.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

LCN8 (HGNC:27038): (lipocalin 8) Members of the lipocalin family, such as LCN8, have a common structure consisting of an 8-stranded antiparallel beta-barrel that forms a cup-shaped ligand-binding pocket or calyx. Lipocalins generally bind small hydrophobic ligands and transport them to specific cells (Suzuki et al., 2004 [PubMed 15363845]).[supplied by OMIM, Aug 2009]

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/exons	MANE	Protein	UniProt
LCN8	NM_178469.4	c.148T>A	p.Tyr50Asn	missense_variant	2/7	ENST00000371688.8	NP_848564.2
LCN8	NM_001345934.2	c.217T>A	p.Tyr73Asn	missense_variant	2/7		NP_001332863.1
LCN8	XM_017014272.3	c.217T>A	p.Tyr73Asn	missense_variant	2/6		XP_016869761.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCN8	ENST00000371688.8	c.148T>A	p.Tyr50Asn	missense_variant	2/7	1	NM_178469.4	ENSP00000360753	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460950 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726692

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

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.: 33

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

May 11, 2022

The c.148T>A (p.Y50N) alteration is located in exon 2 (coding exon 2) of the LCN8 gene. This alteration results from a T to A substitution at nucleotide position 148, causing the tyrosine (Y) at amino acid position 50 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.021	.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.4	D;.
REVEL	Benign	0.088
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.60
MutPred		0.64		.;Gain of disorder (P = 0.0102);
MVP		0.45
MPC		0.66
ClinPred		0.96	D
GERP RS		2.3
Varity_R		0.23
gMVP		0.59

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: rs1301057589; hg19: chr9-139651497;