1-77916129-CTGAGG-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PM2BS2
The NM_144573.4(NEXN):c.25_27+2delGAGGT(p.Glu9del) variant causes a splice donor, conservative inframe deletion, splice region, intron change. The variant allele was found at a frequency of 0.00000344 in 1,452,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E9E) has been classified as Uncertain significance.
Frequency
Consequence
NM_144573.4 splice_donor, conservative_inframe_deletion, splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.25_27+2delGAGGT | p.Glu9del | splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant | 2/13 | ENST00000334785.12 | NP_653174.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.25_27+2delGAGGT | p.Glu9del | splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant | 2/13 | 1 | NM_144573.4 | ENSP00000333938.7 | ||
NEXN | ENST00000401035.7 | c.25_27+2delGAGGT | p.Glu9del | splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant | 2/9 | 1 | ENSP00000383814.3 | |||
NEXN | ENST00000330010.12 | c.25_27+2delGAGGT | p.Glu9del | splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant | 2/12 | 2 | ENSP00000327363.8 | |||
NEXN | ENST00000440324.5 | c.25_27+2delGAGGT | p.Glu9del | splice_donor_variant, conservative_inframe_deletion, splice_region_variant, intron_variant | 2/10 | 5 | ENSP00000411902.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000818 AC: 2AN: 244582Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132640
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1452972Hom.: 0 AF XY: 0.00000277 AC XY: 2AN XY: 722790
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 09, 2023 | The c.25_27+2delGAGGT variant results from a deletion of 5 nucleotides between positions 25 and 27+2 and involves the canonical splice donor site after coding exon 1 of the NEXN gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The canonical splice donor site is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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. Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at