rs199476399
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_014476.6(PDLIM3):c.178_179insCA(p.Met60ThrfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
PDLIM3
NM_014476.6 frameshift
NM_014476.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.61
Genes affected
PDLIM3 (HGNC:20767): (PDZ and LIM domain 3) The protein encoded by this gene contains a PDZ domain and a LIM domain, indicating that it may be involved in cytoskeletal assembly. In support of this, the encoded protein has been shown to bind the spectrin-like repeats of alpha-actinin-2 and to colocalize with alpha-actinin-2 at the Z lines of skeletal muscle. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Aberrant alternative splicing of this gene may play a role in myotonic dystrophy. [provided by RefSeq, Apr 2012]
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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 | UniProt |
---|---|---|---|---|---|---|---|
PDLIM3 | NM_014476.6 | c.178_179insCA | p.Met60ThrfsTer2 | frameshift_variant | 2/8 | ENST00000284767.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDLIM3 | ENST00000284767.12 | c.178_179insCA | p.Met60ThrfsTer2 | frameshift_variant | 2/8 | 5 | NM_014476.6 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251366Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135858
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461828Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14AN XY: 727232
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary dilated cardiomyopathy;C0007194:Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2022 | This variant is also known as 178insCA. 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. ClinVar contains an entry for this variant (Variation ID: 31837). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 17254821). This variant is present in population databases (rs199476399, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Met60Thrfs*2) in the PDLIM3 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in PDLIM3 cause disease. - |
not provided Other:1
not provided, no classification provided | curation | Leiden Muscular Dystrophy (PDLIM3) | Apr 20, 2012 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at