4-16502776-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001290.5(LDB2):c.989C>A(p.Ala330Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LDB2 NM_001290.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.09

Genes affected

LDB2 (HGNC:6533): (LIM domain binding 2) The protein encoded by this gene belongs to the LIM-domain binding family. Members of this family are characterized by a conserved nuclear localization sequence, an amino-terminal homodimerization domain and a carboxy-terminal LIM interaction domain. These proteins function as adapter molecules to allow assembly of transcriptional regulatory complexes. Genetic association studies suggest functions for this gene in rhegmatogenous retinal detachment and coronary artery disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDB2	NM_001290.5	c.989C>A	p.Ala330Glu	missense_variant	8/8	ENST00000304523.10
LOC105374505	XR_007058068.1	n.209-33854G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDB2	ENST00000304523.10	c.989C>A	p.Ala330Glu	missense_variant	8/8	1	NM_001290.5	P4
	ENST00000512370.5	n.181-9157G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

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

Dec 05, 2022

The c.989C>A (p.A330E) alteration is located in exon 8 (coding exon 8) of the LDB2 gene. This alteration results from a C to A substitution at nucleotide position 989, causing the alanine (A) at amino acid position 330 to be replaced by a glutamic acid (E). 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	0.80
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	28
Dann	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.021	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.93	P;P
Vest4		0.81
MutPred		0.54		.;Gain of solvent accessibility (P = 0.005);
MVP		0.52
MPC		1.7
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.46
gMVP		0.75

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: chr4-16504399;