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

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NEXN
NM_144573.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.80

Publications

0 publications found
Variant links:
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]
NEXN Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy 1CC
    Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • hypertrophic cardiomyopathy 20
    Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.09467456 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEXNNM_144573.4 linkc.28-2A>G splice_acceptor_variant, intron_variant Intron 2 of 12 ENST00000334785.12 NP_653174.3 Q0ZGT2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEXNENST00000334785.12 linkc.28-2A>G splice_acceptor_variant, intron_variant Intron 2 of 12 1 NM_144573.4 ENSP00000333938.7 Q0ZGT2-1
NEXNENST00000401035.7 linkc.28-396A>G intron_variant Intron 2 of 8 1 ENSP00000383814.3 E7ETM8
NEXNENST00000330010.12 linkc.28-396A>G intron_variant Intron 2 of 11 2 ENSP00000327363.8 Q0ZGT2-4
NEXNENST00000440324.5 linkc.28-2A>G splice_acceptor_variant, intron_variant Intron 2 of 9 5 ENSP00000411902.1 E7EUA0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000804
AC:
2
AN:
248772
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1455544
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
724424
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33344
American (AMR)
AF:
0.00
AC:
0
AN:
44652
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26058
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39566
South Asian (SAS)
AF:
0.0000233
AC:
2
AN:
85686
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53382
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1106922
Other (OTH)
AF:
0.00
AC:
0
AN:
60184
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00000843
Hom.:
0
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
May 30, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
34
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
PhyloP100
8.8
GERP RS
5.3
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.83
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.52
Position offset: 1
DS_AL_spliceai
0.83
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs751731904; hg19: chr1-78383249; API