1-77926544-A-G
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2
The NM_144573.4(NEXN):āc.620A>Gā(p.Asp207Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.000034 ( 0 hom. )
Consequence
NEXN
NM_144573.4 missense
NM_144573.4 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 8.64
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000335 (49/1461582) while in subpopulation MID AF= 0.00139 (8/5764). AF 95% confidence interval is 0.00069. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 49 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.620A>G | p.Asp207Gly | missense_variant | 7/13 | ENST00000334785.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.620A>G | p.Asp207Gly | missense_variant | 7/13 | 1 | NM_144573.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249226Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135216
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GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461582Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727104
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74482
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 19, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 12, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: "Benign"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 520305). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25979592). This variant is present in population databases (rs570946423, gnomAD 0.006%). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 207 of the NEXN protein (p.Asp207Gly). - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 17, 2019 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2024 | The p.D207G variant (also known as c.620A>G), located in coding exon 6 of the NEXN gene, results from an A to G substitution at nucleotide position 620. The aspartic acid at codon 207 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was detected in an individual with hypertrophic cardiomyopathy (HCM) who also had a variant in another cardiac-related gene (Waldmüller S et al. Mol. Cell. Probes. 2015;29:308-14). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;N;D
REVEL
Benign
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.77
.;.;P;.
Vest4
0.34, 0.33
MVP
MPC
0.13
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at