10-86668319-A-C

Variant names:

• chr10-86668319-A-C
• rs2675692
• ENST00000443292.2:c.1487-350A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001368064.1(LDB3):​c.-23-350A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,996 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.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDB3 NM_001368064.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.687
• Publications: 4 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):

• dilated cardiomyopathy

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: ClinGen
• myofibrillar myopathy 4

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368064.1. 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
	LDB3	NM_001368064.1		c.-23-350A>C		intron	N/A	NP_001354993.1	V5T7C5
	LDB3	NM_001368063.1		c.-23-350A>C		intron	N/A	NP_001354992.1	A0A0S2Z501
	LDB3	NM_001368068.1		c.-23-350A>C		intron	N/A	NP_001354997.1	A0A0S2Z530

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289258	ENST00000443292.2	TSL:1	c.1487-350A>C		intron	N/A	ENSP00000393132.2	C9JWU6
	LDB3	ENST00000945670.1		c.-25A>C		splice_region	Exon 1 of 13	ENSP00000615729.1
	LDB3	ENST00000945670.1		c.-25A>C		5_prime_UTR	Exon 1 of 13	ENSP00000615729.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 199136 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 106974

African (AFR) AF: 0.00 AC: 0 AN: 5990

American (AMR) AF: 0.00 AC: 0 AN: 11244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4906

East Asian (EAS) AF: 0.00 AC: 0 AN: 9762

South Asian (SAS) AF: 0.00 AC: 0 AN: 34408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 112806

Other (OTH) AF: 0.00 AC: 0 AN: 10362

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 2290

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.15
PhyloP100		-0.69
PromoterAI		0.0054	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2675692; hg19: chr10-88428076;