chr7-128840598-G-A
Variant summary
Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_001458.5(FLNC):c.1600G>A(p.Glu534Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000841 in 1,614,218 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E534Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001458.5 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics, G2P
- myofibrillar myopathy 5Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, G2P
- hypertrophic cardiomyopathy 26Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
- distal myopathy with posterior leg and anterior hand involvementInheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
- familial isolated restrictive cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- heart conduction diseaseInheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp
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ACMG classification
Our verdict: Benign. The variant received -11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000788 AC: 120AN: 152218Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.000785 AC: 196AN: 249574 AF XY: 0.000783 show subpopulations
GnomAD4 exome AF: 0.000847 AC: 1238AN: 1461882Hom.: 3 Cov.: 33 AF XY: 0.000850 AC XY: 618AN XY: 727240 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000788 AC: 120AN: 152336Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59AN XY: 74488 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
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This variant is associated with the following publications: (PMID: 27296017, 28008999) -
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FLNC: BS1 -
not specified Benign:3
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Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26 Benign:1
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Cardiomyopathy Benign:1
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FLNC-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
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. -
Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at