rs137853197

chr1-77942756-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_Strong PP5 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:7
• Conservation: PhyloP100: 9.32

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]

ACMG classification

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: {Likely_pathogenic=2, Uncertain_significance=7, Pathogenic=1}. Variant chr1-77942756-A-G is described in Lovd as [Likely_pathogenic].
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4	c.1955A>G	p.Tyr652Cys	missense_variant	13/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12	c.1955A>G	p.Tyr652Cys	missense_variant	13/13	1	NM_144573.4	P3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152170 Hom.: 0 Cov.: 32

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: 18 AN: 248554 Hom.: 0 AF XY: 0.0000741 AC XY: 10 AN XY: 134868

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.: 0 Cov.: 32 AF XY: 0.000154 AC XY: 112 AN XY: 727056

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: 15 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74344

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.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dilated cardiomyopathy 1CC Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
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. -

not provided Uncertain:3

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	Revvity Omics, Revvity	Aug 14, 2023	- -
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. -

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

- -

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 29, 2015

- -

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

Invitae

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	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
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	D
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

Other links and lift over

dbSNP: rs137853197; hg19: chr1-78408441;