4-16511990-C-T

Variant names:

• chr4-16511990-C-T
• rs375403171
• NM_001290.5:c.730G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001290.5(LDB2):​c.730G>A​(p.Ala244Thr) 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 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. A244S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDB2 NM_001290.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

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]

ENSG00000248138 (HGNC:58741):

LOC105374505 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37772527).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB2	NM_001290.5	MANE Select	c.730G>A	p.Ala244Thr	missense	Exon 6 of 8	NP_001281.1	O43679-1
	LDB2	NM_001304434.2		c.730G>A	p.Ala244Thr	missense	Exon 6 of 8	NP_001291363.1	G5E9Y7
	LDB2	NM_001130834.3		c.730G>A	p.Ala244Thr	missense	Exon 6 of 9	NP_001124306.1	O43679-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB2	ENST00000304523.10	TSL:1 MANE Select	c.730G>A	p.Ala244Thr	missense	Exon 6 of 8	ENSP00000306772.5	O43679-1
	LDB2	ENST00000441778.6	TSL:1	c.730G>A	p.Ala244Thr	missense	Exon 6 of 9	ENSP00000392089.2	O43679-2
	LDB2	ENST00000502640.5	TSL:1	c.730G>A	p.Ala244Thr	missense	Exon 6 of 8	ENSP00000423963.1	E9PFI4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250388 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460662 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726690

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111280

Other (OTH) AF: 0.00 AC: 0 AN: 60316

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.22
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.015	B
Vest4		0.60
MutPred		0.71		Loss of glycosylation at P246 (P = 0.009)
MVP		0.29
MPC		0.86
ClinPred		0.64	D
GERP RS		6.1
Varity_R		0.13
gMVP		0.74
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs375403171; hg19: chr4-16513613; COSMIC: COSV100453064; COSMIC: COSV100453064;