rs45578640

Variant names:

• chr10-86726174-C-T
• rs45578640
• NM_007078.3:c.2016C>T
• LDB3 p.Cys672Cys

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007078.3(LDB3):​c.2016C>T​(p.Cys672Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,613,954 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: LDB3 NM_007078.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.911
• Publications: 2 publications found

Genes affected

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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

ENSG00000272631 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-86726174-C-T is Benign according to our data. Variant chr10-86726174-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.911 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00274 (417/152268) while in subpopulation NFE AF = 0.00501 (341/68012). AF 95% confidence interval is 0.00457. There are 1 homozygotes in GnomAd4. There are 198 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 26 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007078.3. 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_007078.3	MANE Select	c.2016C>T	p.Cys672Cys	synonymous	Exon 13 of 14	NP_009009.1	O75112-1
	LDB3	NM_001171610.2		c.2031C>T	p.Cys677Cys	synonymous	Exon 13 of 14	NP_001165081.1	O75112-7
	LDB3	NM_001368066.1		c.1875C>T	p.Cys625Cys	synonymous	Exon 14 of 15	NP_001354995.1	A0A8I5KV04

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDB3	ENST00000361373.9	TSL:1 MANE Select	c.2016C>T	p.Cys672Cys	synonymous	Exon 13 of 14	ENSP00000355296.3	O75112-1
	LDB3	ENST00000477489.1	TSL:1	c.156C>T	p.Cys52Cys	synonymous	Exon 2 of 2	ENSP00000485538.1	A0A096LPD7
	LDB3	ENST00000945680.1		c.2220C>T	p.Cys740Cys	synonymous	Exon 13 of 14	ENSP00000615739.1

Frequencies

GnomAD3 genomes AF: 0.00274 AC: 417 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00248 AC: 623 AN: 251462 AF XY: 0.00224

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00488

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00466 AC: 6818 AN: 1461686 Hom.: 26 Cov.: 31 AF XY: 0.00451 AC XY: 3279 AN XY: 727142

African (AFR) AF: 0.000687 AC: 23 AN: 33472

American (AMR) AF: 0.000917 AC: 41 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00168 AC: 44 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53418

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.00585 AC: 6505 AN: 1111938

Other (OTH) AF: 0.00306 AC: 185 AN: 60384

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152268 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74446

African (AFR) AF: 0.000986 AC: 41 AN: 41562

American (AMR) AF: 0.00163 AC: 25 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00501 AC: 341 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00405 Hom.: 1

Bravo AF: 0.00262

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00462

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LDB3-related disorder (1)
-	-	1	Myofibrillar myopathy 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.56
DANN	Benign	0.57
PhyloP100		-0.91
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs45578640;

hg19: chr10-88485931;