NM_144573.4:c.613G>A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_144573.4(NEXN):c.613G>A(p.Glu205Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000577 in 1,613,730 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_144573.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000348 AC: 53AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000225 AC: 56AN: 249122Hom.: 0 AF XY: 0.000229 AC XY: 31AN XY: 135170
GnomAD4 exome AF: 0.000601 AC: 878AN: 1461506Hom.: 1 Cov.: 31 AF XY: 0.000598 AC XY: 435AN XY: 727066
GnomAD4 genome AF: 0.000348 AC: 53AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74436
ClinVar
Submissions by phenotype
not specified Uncertain:2
The Glu205Lys variant in NEXN has not been reported in the literature, but has b een identified by our laboratory in 1 individual with HCM and in 1 infant with L VNC, hypotonia and motor delay who carried a likely pathogenic variant in anothe r gene. This variant has also been identified in 4/8168 European American chromo somes from a broad population by the NHLBI Exome Sequencing Project (http://evs. gs.washington.edu/EVS/; dbSNP rs201447781). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional informat ion is needed to fully assess the clinical significance of the Glu205Lys variant . -
Variant summary: NEXN c.613G>A (p.Glu205Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249122 control chromosomes. The observed variant frequency is approximately 9-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEXN causing Cardiomyopathy phenotype (2.5e-05). c.613G>A has been reported in the literature in individuals affected with Brugada syndrome, sudden cardiac death, or surviving cardiac arrest, frequently reported as VUS, once as possibly pathogenic, but in the presence of other variants realted to cardiovascular disease (e.g. Seidelmann_2018, Mellor_2017, Salfati_2019, Murphy_2024). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28600387, 38489124, 31847883, 28087566). ClinVar contains an entry for this variant (Variation ID: 47908). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Cardiomyopathy Uncertain:1
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not provided Uncertain:1
Reported in two individuals with sudden cardiac arrest/death and non-specific cardiac disease; however, each individual also harbored other cardiogenetic variants (Mellor et al., 2017; Seidelmann et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28087566, 28600387) -
Cardiovascular phenotype Uncertain:1
The c.613G>A (p.E205K) alteration is located in exon 7 (coding exon 6) of the NEXN gene. This alteration results from a G to A substitution at nucleotide position 613, causing the glutamic acid (E) at amino acid position 205 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 205 of the NEXN protein (p.Glu205Lys). This variant is present in population databases (rs201447781, gnomAD 0.05%). This missense change has been observed in individual(s) with Brugada syndrome and/or cardiomyopathy (PMID: 31847883, 38489124). ClinVar contains an entry for this variant (Variation ID: 47908). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NEXN protein function. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at