rs2675693

Variant names:

• chr10-86667386-C-T
• rs2675693
• ENST00000443292.2:c.1486+538C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000443292.2(ENSG00000289258):​c.1486+538C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 152,166 control chromosomes in the GnomAD database, including 999 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.099 (999 hom., cov: 33)
• Consequence: ENSG00000289258 ENST00000443292.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.63
• Publications: 1 publications found

Genes affected

ENSG00000289258 (HGNC:):

LDB3 (HGNC:15710): (LIM domain binding 3) This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains. [provided by RefSeq, Jan 2010]

LDB3 Gene-Disease associations (from GenCC):

• myofibrillar myopathy 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDB3	NM_001368064.1	c.-24+538C>T		intron_variant	Intron 1 of 12		NP_001354993.1
LDB3	NM_001368063.1	c.-24+538C>T		intron_variant	Intron 1 of 7		NP_001354992.1
LDB3	NM_001368068.1	c.-24+538C>T		intron_variant	Intron 1 of 8		NP_001354997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289258	ENST00000443292.2	c.1486+538C>T		intron_variant	Intron 11 of 17	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.0989 AC: 15040 AN: 152046 Hom.: 1000 Cov.: 33

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.112

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0988 AC: 15033 AN: 152166 Hom.: 999 Cov.: 33 AF XY: 0.0982 AC XY: 7309 AN XY: 74392

African (AFR) AF: 0.0293 AC: 1216 AN: 41542

American (AMR) AF: 0.115 AC: 1758 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 491 AN: 3470

East Asian (EAS) AF: 0.0244 AC: 126 AN: 5168

South Asian (SAS) AF: 0.0332 AC: 160 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1269 AN: 10598

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9455 AN: 67976

Other (OTH) AF: 0.111 AC: 234 AN: 2110

Alfa AF: 0.113 Hom.: 146

Bravo AF: 0.0960

Asia WGS AF: 0.0340 AC: 117 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.64
PhyloP100		-2.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2675693; hg19: chr10-88427143;