2-74497982-G-A

Variant names:

• chr2-74497982-G-A
• rs747140609
• NM_001282430.2:c.542C>T

Variant summary

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

The NM_001282430.2(LBX2):​c.542C>T​(p.Ala181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,605,624 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: LBX2 NM_001282430.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.22

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]

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=0.07356611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBX2	NM_001282430.2	c.542C>T	p.Ala181Val	missense_variant	Exon 2 of 2	ENST00000377566.9	NP_001269359.1
LBX2	NM_001009812.2	c.530C>T	p.Ala177Val	missense_variant	Exon 2 of 2		NP_001009812.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBX2	ENST00000377566.9	c.542C>T	p.Ala181Val	missense_variant	Exon 2 of 2	1	NM_001282430.2	ENSP00000366789.4
LBX2	ENST00000460508.3	c.530C>T	p.Ala177Val	missense_variant	Exon 2 of 2	1		ENSP00000417116.2
LBX2	ENST00000550249.2	n.836C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
LBX2	ENST00000341396	c.*187C>T		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000450229.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152282 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000142 AC: 35 AN: 246590 Hom.: 0 AF XY: 0.000165 AC XY: 22 AN XY: 133736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000298

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000135

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000114 AC: 166 AN: 1453342 Hom.: 0 Cov.: 29 AF XY: 0.000112 AC XY: 81 AN XY: 721538

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.000270

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000221

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000114

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74406

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.530C>T (p.A177V) alteration is located in exon 2 (coding exon 2) of the LBX2 gene. This alteration results from a C to T substitution at nucleotide position 530, causing the alanine (A) at amino acid position 177 to be replaced by a valine (V). 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	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	4.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0024	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.51	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.14
Sift	Benign	0.031	D;D
Sift4G	Benign	0.16	T;T
Polyphen		0.019	B;B
Vest4		0.049
MutPred		0.26		Loss of catalytic residue at A181 (P = 0.0649);.;
MVP		0.53
MPC		0.49
ClinPred		0.033	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.27

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: rs747140609; hg19: chr2-74725109;