1-156130740-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000368300.9(LMNA):c.480C>T(p.Gly160=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000269 in 1,452,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G160G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
LMNA
ENST00000368300.9 synonymous
ENST00000368300.9 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -4.64
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.480C>T | p.Gly160= | synonymous_variant | 2/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.480C>T | p.Gly160= | synonymous_variant | 2/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.480C>T | p.Gly160= | synonymous_variant | 2/12 | 1 | NM_170707.4 | ENSP00000357283 | P1 | |
| LMNA | ENST00000677389.1 | c.480C>T | p.Gly160= | synonymous_variant | 2/10 | NM_005572.4 | ENSP00000503633 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000861 AC: 2AN: 232328Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 125948
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GnomAD4 exome AF: 0.0000269 AC: 39AN: 1452146Hom.: 0 Cov.: 32 AF XY: 0.0000249 AC XY: 18AN XY: 721704
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 14, 2021 | This synonymous variant does not change the amino acid sequence of the lamin A/C proteins. Splice site prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. A functional study with minigene assay has shown that this variant alters mRNA splicing in vitro (PMID: 28679633). This variant has been reported in an individual affected with idiopathic ventricular fibrillation (PMID: 31453089). However, no abnormal splicing was detected in the RNA sample derived from this individual's peripheral blood cell, indicating that this variant has no impact on splicing in vivo and could not explain the observed phenotype. This variant has been identified in 2/232328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 26, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 28679633). ClinVar contains an entry for this variant (Variation ID: 519479). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is present in population databases (rs758848135, gnomAD 0.002%). This sequence change affects codon 160 of the LMNA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LMNA protein. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This synonymous variant does not change the amino acid sequence of the lamin A/C proteins. Splice site prediction tools and conservation analysis are inconclusive regarding the impact of this variant on RNA splicing. A functional study with minigene assay has shown that this variant alters mRNA splicing in vitro (PMID: 28679633). This variant has been reported in an individual affected with idiopathic ventricular fibrillation (PMID: 31453089). However, no abnormal splicing was detected in the RNA sample derived from this individual's peripheral blood cell, indicating that this variant has no impact on splicing in vivo and could not explain the observed phenotype. This variant has been identified in 2/232328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 04, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at