chr1-77933402-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_144573.4(NEXN):​c.1174C>T​(p.Arg392*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000416 in 1,612,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

NEXN
NM_144573.4 stop_gained

Scores

4
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:7

Conservation

PhyloP100: 3.56

Publications

9 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 5 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 1-77933402-C-T is Pathogenic according to our data. Variant chr1-77933402-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229051.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NEXNNM_144573.4 linkc.1174C>T p.Arg392* stop_gained Exon 10 of 13 ENST00000334785.12 NP_653174.3 Q0ZGT2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NEXNENST00000334785.12 linkc.1174C>T p.Arg392* stop_gained Exon 10 of 13 1 NM_144573.4 ENSP00000333938.7 Q0ZGT2-1

Frequencies

GnomAD3 genomes
AF:
0.0000461
AC:
7
AN:
151768
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000209
Gnomad FIN
AF:
0.0000950
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000201
AC:
5
AN:
248708
AF XY:
0.0000296
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:
0.0000443
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000411
AC:
60
AN:
1460656
Hom.:
0
Cov.:
30
AF XY:
0.0000440
AC XY:
32
AN XY:
726630
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33444
American (AMR)
AF:
0.00
AC:
0
AN:
44672
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26106
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39634
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85966
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000486
AC:
54
AN:
1111322
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60342
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
3
7
10
14
17
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
AF:
0.0000461
AC:
7
AN:
151768
Hom.:
0
Cov.:
33
AF XY:
0.0000405
AC XY:
3
AN XY:
74088
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41282
American (AMR)
AF:
0.00
AC:
0
AN:
15230
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.000209
AC:
1
AN:
4796
European-Finnish (FIN)
AF:
0.0000950
AC:
1
AN:
10524
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000736
AC:
5
AN:
67974
Other (OTH)
AF:
0.00
AC:
0
AN:
2076
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000604
ExAC
AF:
0.00000828
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Pathogenic:1Uncertain:1
Nov 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg392*) in the NEXN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776). This variant is present in population databases (rs750076188, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25163546, 33949776). ClinVar contains an entry for this variant (Variation ID: 229051). For these reasons, this variant has been classified as Pathogenic. -

Nov 17, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:2
Jan 19, 2022
AiLife Diagnostics, AiLife Diagnostics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

The NEXN p.Arg392X variant was identified in a study performing NGS on 639 patients with dilated cardiomyopathy (Haas_2014_PMID:25163546). It was not identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs750076188) and Clinvar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 7 of 280056 chromosomes at a frequency of 0.000025 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 6 of 128186 chromosomes (freq: 0.000047) and European (Finnish) in 1 of 25012 chromosomes (freq: 0.00004); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Other or South Asian populations. The p.Arg392X variant leads to a premature stop codon at position 392 which is predicted to lead to a truncated or absent protein and loss of function. The role of NEXN loss of function variants in disease is still unclear, however NEXN knock-out mice studies display a cardiomyopathy phenotype (Aherrahrou_2016_PMID:26659360). Further, MutationTaster predicts the variant to be disease-causing (prob: 1). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Primary dilated cardiomyopathy Pathogenic:1
Nov 05, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change in NEXN is a nonsense variant predicted to cause a premature stop codon, p.(Arg392*), in biologically relevant exon 10/16 leading to nonsense-mediated decay in a gene in which there is emerging evidence for loss of function as the mechanism of disease (PMID: 19881492, 26659360, 31983221, 32058062, 32635769, 32814711, 32870709, 33949776, 35166435). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.005% (6/128,186 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy (DCM). This variant has been reported heterozygous in at least eight probands with DCM (including one proband with a pathogenic FLNC variant), at least one proband with hypertrophic cardiomyopathy and one proband with an unknown cardiomyopathy (PMID: 25163546, 28008423, 30847666, 31983221, 32880476, 35581137, ClinVar: SCV001572576.1, SCV001366672.2). This variant has been detected homozygous in at least one foetus with hydrops and abnormal cardiac function (PMID: 33949776). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Moderate, PS4_Moderate, PM2_Supporting, PM3_Supporting. -

CARDIOMYOPATHY, DILATED, 2M Pathogenic:1
Jul 08, 2025
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

not specified Uncertain:1
Apr 23, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg392X v ariant in NEXN has not been previously reported in individuals with cardiomyopat hy, but has been identified in 1/64806 of European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 392, which is predicted to l ead to a truncated or absent protein. Although the severe nature of this change increases the likelihood that the variant is pathogenic, the NEXN gene has not b een widely studied and the spectrum of variants leading to disease is not well-d efined. Loss of NEXN function has been shown to cause DCM in zebrafish (Hassel 2 009, Wang 2010) and loss of function variants have been identified in individual s with a range of cardiomyopathies (LMM unpublished data); however, it remains u nclear if one or both copies of the gene need to be affected to cause disease. I n summary, while there is some suspicion for a pathogenic role, the clinical sig nificance of the p.Arg392X variant is uncertain. -

Dilated cardiomyopathy 1CC Uncertain:1
May 23, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. -

Hypertrophic cardiomyopathy Uncertain:1
Feb 26, 2021
Loeys Lab, Universiteit Antwerpen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change results in a frameshift variant in the NEXN gene (p.(Arg392*)). This variant is present in population databases with a prevalence of 7/276332in GnomAD. Loss of function of NEXN caused DCM in zebrafish (PMID: 19881492). This variant has not been reported in the literature. We identified the variant in 3 unrelated patients: two patients with DCM and one patient with HCM. In the HCM family a second individual with HCM also carried the variant (limited data on segregation:PP1weak). No segregation data are available for the DCM families. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met). -

Cardiovascular phenotype Uncertain:1
Aug 29, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R392* variant (also known as c.1174C>T), located in coding exon 9 of the NEXN gene, results from a C to T substitution at nucleotide position 1174. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant has been detected in the homozygous state in an individual with severe early-onset and fatal dilated cardiomyopathy (DCM) whose heterozygous parents were unaffected (Bruyndonckx L et al. Am J Med Genet A, 2021 08;185:2464-2470). This alteration has also been detected (presumed heterozygous) in individuals from DCM and hypertrophic cardiomyopathy cohorts; however, clinical details were limited and additional alterations in cardiac-related genes were identified in some cases (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Begay RL et al. JACC Basic Transl Sci. 2016 Aug;1(5):344-359; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Verdonschot JAJ et al. Circ Genom Precis Med, 2020 10;13:476-487; Boen HM et al. J Heart Lung Transplant. 2022 Sep;41(9):1218-1227). 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. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive NEXN-related cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant NEXN-related cardiomyopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
40
DANN
Uncertain
1.0
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.94
D
PhyloP100
3.6
Vest4
0.41
GERP RS
5.0
Mutation Taster
=3/197
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs750076188; hg19: chr1-78399087; API