2-74497935-C-T

Variant names:

• chr2-74497935-C-T
• rs760051483
• NM_001282430.2:c.589G>A

Variant summary

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

The NM_001282430.2(LBX2):​c.589G>A​(p.Asp197Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000778 in 1,414,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D197H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000078 (0 hom.)
• Consequence: LBX2 NM_001282430.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3071434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBX2	NM_001282430.2	c.589G>A	p.Asp197Asn	missense_variant	Exon 2 of 2	ENST00000377566.9	NP_001269359.1
LBX2	NM_001009812.2	c.577G>A	p.Asp193Asn	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.589G>A	p.Asp197Asn	missense_variant	Exon 2 of 2	1	NM_001282430.2	ENSP00000366789.4
LBX2	ENST00000460508.3	c.577G>A	p.Asp193Asn	missense_variant	Exon 2 of 2	1		ENSP00000417116.2
LBX2	ENST00000550249.2	n.883G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
LBX2	ENST00000341396	c.*234G>A		3_prime_UTR_variant	Exon 2 of 2	3		ENSP00000450229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000464 AC: 1 AN: 215430 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 117364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000400

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000778 AC: 11 AN: 1414500 Hom.: 0 Cov.: 29 AF XY: 0.0000129 AC XY: 9 AN XY: 698252

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: 0.000136

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0089	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.021	D;D
Polyphen		0.99	D;D
Vest4		0.12
MutPred		0.28		Loss of stability (P = 0.4223);.;
MVP		0.72
MPC		1.1
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.11
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760051483; hg19: chr2-74725062;