1-77917564-A-G
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_144573.4(NEXN):c.28-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_144573.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: MODERATE Submitted by: ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1CCInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypertrophic cardiomyopathy 20Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.28-2A>G | splice_acceptor_variant, intron_variant | Intron 2 of 12 | 1 | NM_144573.4 | ENSP00000333938.7 | |||
NEXN | ENST00000401035.7 | c.28-396A>G | intron_variant | Intron 2 of 8 | 1 | ENSP00000383814.3 | ||||
NEXN | ENST00000330010.12 | c.28-396A>G | intron_variant | Intron 2 of 11 | 2 | ENSP00000327363.8 | ||||
NEXN | ENST00000440324.5 | c.28-2A>G | splice_acceptor_variant, intron_variant | Intron 2 of 9 | 5 | ENSP00000411902.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.00000804 AC: 2AN: 248772 AF XY: 0.0000148 show subpopulations
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1455544Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2AN XY: 724424 show subpopulations
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
The c.28-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 2 in the NEXN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, this region of the NEXN gene is excluded from other biologically relevant NEXN transcripts. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at