chr1-77942823-GAATT-G
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2
The NM_144573.4(NEXN):c.2026_*1del variant causes a frameshift, stop lost change. The variant allele was found at a frequency of 0.0000162 in 1,605,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
NEXN
NM_144573.4 frameshift, stop_lost
NM_144573.4 frameshift, stop_lost
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.88
Genes affected
NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM4
Stoplost variant in NM_144573.4 Downstream stopcodon found after 64 codons.
BS2
High AC in GnomAdExome4 at 23 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.2026_*1del | frameshift_variant, stop_lost | 13/13 | ENST00000334785.12 | NP_653174.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.2026_*1del | frameshift_variant, stop_lost | 13/13 | 1 | NM_144573.4 | ENSP00000333938 | P3 | ||
NEXN | ENST00000342754.5 | c.1716+9_1716+12del | splice_donor_region_variant, intron_variant | 1 | ENSP00000343928 | |||||
NEXN | ENST00000330010.12 | c.1834_*1del | frameshift_variant, stop_lost | 12/12 | 2 | ENSP00000327363 | A1 | |||
NEXN | ENST00000480732.2 | n.1600_1603del | non_coding_transcript_exon_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152070Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000568 AC: 14AN: 246376Hom.: 0 AF XY: 0.0000523 AC XY: 7AN XY: 133822
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GnomAD4 exome AF: 0.0000158 AC: 23AN: 1453420Hom.: 0 AF XY: 0.0000166 AC XY: 12AN XY: 723448
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152070Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 11, 2017 | The p.X676HisextX9 variant in NEXN has not been previously reported in individua ls with cardiomyopathy but has been identified in 13/34248 of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs794729094). This variant deletes the stop codon, replaces it with a Histi dine and extends the protein by 8 amino acids. The impact of this change on prot ein function is unknown. NEXN variants have been described in individuals with D CM and HCM but they are rare and overall poorly studied. In summary, the clinica l significance of the p.X676HisextX9 variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 04, 2020 | Has not been previously published as pathogenic or benign to our knowledge - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2023 | The c.2026_*1delTAAT variant (also known as p.*676Hext*8) is located in coding exon 12 of the NEXN gene. This variant results from a deletion of 4 nucleotides from position 2026 into the 3' untranslated region. This alteration disrupts the stop codon of the NEXN gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 8 amino acids. The exact functional effect of the additional amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2022 | This variant is present in population databases (rs764404383, gnomAD 0.04%). 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 201946). This variant has not been reported in the literature in individuals affected with NEXN-related conditions. This sequence change disrupts the translational stop signal of the NEXN mRNA. It is expected to extend the length of the NEXN protein by 8 additional amino acid residues. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at