rs876657928

Positions:

• chr1-77942618-CAGG-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_144573.4(NEXN):​c.1820_1822del​(p.Gly607del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: NEXN NM_144573.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 10.0

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAdExome4 at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEXN	NM_144573.4	c.1820_1822del	p.Gly607del	inframe_deletion	13/13	ENST00000334785.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEXN	ENST00000334785.12	c.1820_1822del	p.Gly607del	inframe_deletion	13/13	1	NM_144573.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 248994 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000308 AC: 45 AN: 1461652 Hom.: 0 AF XY: 0.0000344 AC XY: 25 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 01, 2015

The p.Gly607del variant in NEXN has not been previously reported in individuals with cardiomyopathy but has been identified in 3/66474 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This var iant is a deletion of 1 amino acid at position 607. It is unclear if this deleti on will impact the protein. In summary, the clinical significance of the p.Gly60 7del variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 12, 2017

A variant of uncertain significance has been identified in the NEXN gene. The c.1820_1822delGAG variant has not been published as pathogenic or been reported as benign to our knowledge. The c.1820_1822delGAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1820_1822delGAG variant results in an in-frame deletion of a Glycine residue at codon 607, denoted p.Gly607del, and does not result in a shift in the reading frame or a premature stop codon. No nearby in-frame deletions in the NEXN gene have been reported in the Human Gene Mutation Database (HGMD) in association with cardiomyopathy, and the majority of variants in the NEXN gene reported in HGMD are missense variants (Stenson et al., 2014). However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2022

The c.1820_1822delGAG variant (also known as p.G607del) is located in coding exon 12 of the NEXN gene. This variant results from an in-frame GAG deletion at nucleotide positions 1820 to 1822. This results in the in-frame deletion of a glycine residue at codon 607. This variant has been reported in dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) cohorts (Mazzarotto F et al. Circulation, 2020 02;141:387-398; Mazzarotto F et al. Genet Med, 2021 05;23:856-864).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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. -

Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 13, 2022

This variant, c.1820_1822del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Gly607del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774370743, gnomAD 0.006%). This variant has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 31983221, 33500567). ClinVar contains an entry for this variant (Variation ID: 229055). 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. -

Computational scores

Source: dbNSFP v4.3

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: rs876657928; hg19: chr1-78408303;