1-77942756-A-G

Position:

chr1-77942756-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2

The NM_144573.4(NEXN):c.1955A>G(p.Tyr652Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,613,652 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).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

NEXN
NM_144573.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:11

Conservation

PhyloP100: 9.32

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 links:

NEXN (HGNC:):

NEXN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 1-77942756-A-G is Pathogenic according to our data. Variant chr1-77942756-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=11, Pathogenic=1, Likely_pathogenic=2}. Variant chr1-77942756-A-G is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEXN	NM_144573.4 linkuse as main transcript	c.1955A>G	p.Tyr652Cys	missense_variant	13/13	ENST00000334785.12	NP_653174.3	Q0ZGT2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEXN	ENST00000334785.12 linkuse as main transcript	c.1955A>G	p.Tyr652Cys	missense_variant	13/13	1	NM_144573.4	ENSP00000333938.7		Q0ZGT2-1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000724

AC:

AN:

248554

Hom.:

AF XY:

0.0000741

AC XY:

AN XY:

134868

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 SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000159

AC:

232

AN:

1461482

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000993

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 09, 2024	The p.Tyr652Cys variant in NEXN has been reported in at least 8 individuals with DCM some of whom also had pathogenic variants in other genes that could explain their phenotype, 1 individual with HCM, 1 individual with sudden cardiac death and 1 individual with noncompaction cardiomyopathy (Hassel 2009 PMID: 19881492, Hertz 2016 PMID: 26383259, Kaluke 2017 PMID: 29253866, Minoche 2019 PMID: 29961767, Van Lint 2019 PMID: 30847666, Murdock 2021 PMID: 34363016, LMM internal data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 326) and has been identified in 0.018% (12/68008) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). Functional studies in zebrafish embryos resulted in severely dilated hearts and heart biopsies of 2 individuals with DCM who harbored this variant (and did not have a pathogenic variant identified in a cardiomyopathy related gene) show a disrupted sarcomere (Hassel 2009 PMID: 19881492), suggesting that this variant affects protein function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PS3_Moderate, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	Functional studies suggest this missense variant acts in a dominant-negative manner and leads to a dilated cardiomyopathy phenotype in zebrafish (Hassel et al., 2009), however, further functional evidence is needed to clarify the role of this variant in human disease; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20970104, 31028938, 26187847, 27171814, 23299917, 19881492, 29253866, 26383259, 30847666, 33949776, 29961767, 24503780, 34363016, 35166435, 36935760) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 03, 2024	PP3, PS3_moderate -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 17, 2023	- -

Dilated cardiomyopathy 1CC

Pathogenic:2Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jun 11, 2020	The c.1955A>G (p.Tyr652Cys) variant in the exon 13 of NEXN gene has been reported in 3 individuals with dilated cardiomyopathy (DCM) and 1 individual with sudden cardiac death (SCD) and non-diagnostic right ventricular hypertrophy (PMID: 19881492, 24503780, 26383259). This variant is present at a frequency of 22/279940 in the population database gnomAD suggesting that it could exhibit reduced penetrance. Multiple lines of in silico algorithms have predicted the p.Tyr652Cys change to be deleterious. Functional studies showed that expression of this variant in zebrafish destabilizes cardiac Z-disks and leads to a DCM phenotype (PMID: 19881492). Therefore, this c.1955A>G (p.Tyr652Cys) in the NEXN gene is classified as likely pathogenic with possible reduced penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, functional studies have suggested both dominant negative or loss of function mechanisms (PMID: 19881492, PMID: 20970104, PMID: 32814711). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (33 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated immunoglobulin I-set domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as both a VUS, and as likely pathogenic, and observed in at least 10 individuals with dilated cardiomyopathy (DCM), sudden cardiac death or pancardiomyopathy (ClinVar, cardiodb.org, PMID: 24503780, PMID: 26383259, PMID: 31028938). An additional two individuals had causative variants in either the TTN or MYH7 genes (PMID: 29253866, PMID: 29961767). Another two individuals had ascending aortic aneurysm and dissection, or a family history of cardiac disease, but no indication of DCM themselves (PMID: 34363016). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Overexpression of this variant in zebrafish models has proven it causes disruption to sarcomeric units and destabilizes Z-disks (PMID: 19881492). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Primary dilated cardiomyopathy

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 29, 2015	- -
Uncertain significance, criteria provided, single submitter	research	Lildballe Lab, Aarhus University Hospital	Mar 01, 2024	PP3(m), PM2(sup), PP5(noinf) -

Dilated cardiomyopathy 1S

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Hypertrophic cardiomyopathy 20

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 29, 2022

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 20, 2022

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The p.Y652C variant (also known as c.1955A>G), located in coding exon 12 of the NEXN gene, results from an A to G substitution at nucleotide position 1955. The tyrosine at codon 652 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals from cohorts with dilated cardiomyopathy, non-compaction cardiomyopathy and sudden cardiac death, sometimes in conjunction with variants in other cardiac-related genes (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8; Hassel D et al. Nat. Med., 2009 Nov;15:1281-8; Klauke B et al. PLoS ONE, 2017 Dec;12:e0189489; Hertz CL et al. Int. J. Legal Med., 2016 Jan;130:91-102; van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). One functional study indicated that p.Y652C overexpression in zebrafish disrupts sarcomeric units and destabilizes Z-disks, but the clinical relevance of this overexpression study is unclear (Hassel D et al. Nat Med. 2009;15(11):1281-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2022

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 652 of the NEXN protein (p.Tyr652Cys). This variant is present in population databases (rs137853197, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 19881492, 24503780, 29253866, 30847666). ClinVar contains an entry for this variant (Variation ID: 326). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects NEXN function (PMID: 19881492). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

.;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

4.4

.;H

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.97

MPC

0.35

ClinPred

0.98

GERP RS

5.8

Varity_R

0.93

gMVP

0.90

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.

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