2-74498138-A-G

Variant names:

• chr2-74498138-A-G
• NM_001282430.2:c.386T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001282430.2(LBX2):​c.386T>C​(p.Val129Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V129V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LBX2 NM_001282430.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBX2	NM_001282430.2	c.386T>C	p.Val129Ala	missense_variant	Exon 2 of 2	ENST00000377566.9	NP_001269359.1
LBX2	NM_001009812.2	c.374T>C	p.Val125Ala	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.386T>C	p.Val129Ala	missense_variant	Exon 2 of 2	1	NM_001282430.2	ENSP00000366789.4
LBX2	ENST00000460508.3	c.374T>C	p.Val125Ala	missense_variant	Exon 2 of 2	1		ENSP00000417116.2
LBX2	ENST00000550249.2	n.680T>C		non_coding_transcript_exon_variant	Exon 3 of 3	1
LBX2	ENST00000341396	c.*31T>C		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000450229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374T>C (p.V125A) alteration is located in exon 2 (coding exon 2) of the LBX2 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the valine (V) at amino acid position 125 to be replaced by an alanine (A). 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	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.92
MutPred		0.86		Loss of sheet (P = 0.1158);.;
MVP		0.90
MPC		1.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.50
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74725265;