Genetic Variant LBX2:p.Gly179Ser (chr2-74497989-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001282430.2(LBX2):c.535G>A(p.Gly179Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,607,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LBX2
NM_001282430.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.992

Variant links:

Genes affected

LBX2 (HGNC:15525): (ladybird homeobox 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in several processes, including muscle cell differentiation; positive regulation of convergent extension involved in gastrulation; and positive regulation of non-canonical Wnt signaling pathway. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

LBX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057818323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBX2	NM_001282430.2 link	c.535G>A	p.Gly179Ser	missense_variant	Exon 2 of 2	ENST00000377566.9	NP_001269359.1	Q6XYB7-1
LBX2	NM_001009812.2 link	c.523G>A	p.Gly175Ser	missense_variant	Exon 2 of 2		NP_001009812.1	Q6XYB7-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LBX2	ENST00000377566.9 link	c.535G>A	p.Gly179Ser	missense_variant	Exon 2 of 2	1	NM_001282430.2	ENSP00000366789.4	Q6XYB7-1
LBX2	ENST00000460508.3 link	c.523G>A	p.Gly175Ser	missense_variant	Exon 2 of 2	1		ENSP00000417116.2	Q6XYB7-2
LBX2	ENST00000550249.2 link	n.829G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
LBX2	ENST00000341396 link	c.*180G>A		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000450229.1	G3V218

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722386

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>A (p.G175S) alteration is located in exon 2 (coding exon 2) of the LBX2 gene. This alteration results from a G to A substitution at nucleotide position 523, causing the glycine (G) at amino acid position 175 to be replaced by a serine (S). 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

0.091

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.19

DANN

Benign

0.75

DEOGEN2

Benign

0.0016

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.38

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

-0.090

N;.

PrimateAI

Benign

0.38

PROVEAN

Benign

1.3

N;N

REVEL

Benign

0.15

Sift

Benign

0.38

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.037

B;P

Vest4

0.070

MutPred

0.25

Loss of catalytic residue at G179 (P = 0.0121);.;

MVP

0.34

MPC

0.50

ClinPred

0.14

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.037

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over