dbSNP rs764505909: NEXN:p.Glu528del (chr1-77942120-GAGA-G) – ACMG Classification: Likely_benign (-6 pts)

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 links:

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_144573.4

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152080) while in subpopulation NFE AF= 0.000221 (15/67984). AF 95% confidence interval is 0.000135. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEXN	NM_144573.4 link	c.1582_1584delGAA	p.Glu528del	conservative_inframe_deletion	Exon 12 of 13	ENST00000334785.12	NP_653174.3	Q0ZGT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12 link	c.1582_1584delGAA	p.Glu528del	conservative_inframe_deletion	Exon 12 of 13	1	NM_144573.4	ENSP00000333938.7		Q0ZGT2-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000153

AC:

AN:

248710

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

134980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000335

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1461506

Hom.:

AF XY:

0.000117

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000158

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000283

Hom.:

Bravo

AF:

0.000178

Asia WGS

AF:

0.000867

AC:

AN:

3476

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 07, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 26582918, 37298070) -

Dilated cardiomyopathy 1CC

Uncertain:2

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inframe deletion c.1582_1584del (p.Glu528del) has been observed in individual(s) with dilated cardiomyopathy (Kuhnisch J, et.al.,2019).This variant has been reported to the ClinVar database as Uncertain Significance. The p.Glu528del variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01535% is reported in gnomAD. This p.Glu528del causes deletion of amino acid Glutamic Acid at position 528. For these reasons, this variant has been classified as Uncertain Significance . -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Uncertain:2

Jan 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1582_1584del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Glu528del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770868024, gnomAD 0.03%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31568572; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1572_1574delAGA (p.E525del). ClinVar contains an entry for this variant (Variation ID: 194130). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1Benign:1

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 12, 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.Glu528del variant has been identified in 2 consanguineous families of Middle Eastern anc estry as homozygous in 5 affected siblings (Conference abstract by Al-Hassnan 20 13, LMM unpublished data). This variant has also been identified as heterozygous in 14/65856 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at posi tion 528 from a string of 4 glutamic acids. It is unclear if this deletion will impact the protein. In summary, while there is some suspicion for a pathogenic r ole, the clinical significance of the p.Glu528del variant is uncertain. -

Cardiomyopathy

Uncertain:1

May 13, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1

Jul 03, 2019

Klaassen Lab, Charite University Medicine Berlin

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

NEXN-related disorder

Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NEXN c.1582_1584delGAA variant is predicted to result in an in-frame deletion (p.Glu528del). This variant, also described as c.1572_1574delAGA, has been reported in the homozygous state in at least five individuals with dilated cardiomyopathy (DCM) including two sibling pairs (Al-Hassnan et al. 2013. DOI: 10.1016/j.jsha.2013.03.180; Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572; Al Mansoori et al. 2023. PubMed ID: 37298070). It has also been reported in the heterozygous state in an individual with DCM and left ventricular non-compaction (LVNC) who was homozygous for a splice-altering, loss-of-function variant in the TNNI3 gene (Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572). This variant is reported in 0.036% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1582_1584delGAA variant (also known as p.E528del) is located in coding exon 11 of the NEXN gene. This variant results from an in-frame GAA deletion at nucleotide positions 1582 to 1584. This results in the in-frame deletion of a glutamic acid at codon 528. This variant was reportedly detected in the homozygous state in two siblings with severe, pediatric onset dilated cardiomyopathy (Bruyndonckx L et al. Am J Med Genet A. 2021 08;185(8):2464-2470). This variant, also referred to as p.E525del, was detected in a homozygous proband with DCM and in the heterozygous state in a proband with DCM and noncompaction cardiomyopathy who was also homozygous for a variant in the TNNI3 gene (Kühnisch J. Clin Genet. 2019 12;96(6):549-559). This variant has also been reported in DCM cohorts (Mazzarotto F et al. Circulation, 2020 Feb;141:387-398; Mansoori GA et al. Int J Mol Sci, 2023 May;24:; Koutsofti C et al. Genes (Basel), 2024 Feb;15:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs764505909

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over