5-173232696-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004387.4(NKX2-5):c.848C>A(p.Pro283Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,610,284 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.848C>A | p.Pro283Gln | missense_variant | Exon 2 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.*647C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.*801C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159647.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152260Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000448 AC: 11AN: 245426Hom.: 0 AF XY: 0.0000522 AC XY: 7AN XY: 134032
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1458024Hom.: 0 Cov.: 35 AF XY: 0.00000966 AC XY: 7AN XY: 724746
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74386
ClinVar
Submissions by phenotype
not provided Uncertain:2
Reported in one individual with multiple congenital heart defects (Peng et al., 2010); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 30115; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27152669, 22959235, 21110066, 31983221, 32425884) -
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Ventricular septal defect 3 Pathogenic:1
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Atrial septal defect 7 Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 283 of the NKX2-5 protein (p.Pro283Gln). This variant is present in population databases (rs375086983, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of NKX2-5-related conditions (PMID: 21110066, 31983221, 32425884). ClinVar contains an entry for this variant (Variation ID: 30115). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NKX2-5 protein function with a negative predictive value of 80%. 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. -
Tetralogy of Fallot;C1857586:Conotruncal heart malformations;C2673630:Hypothyroidism, congenital, nongoitrous, 5;C3276096:Atrial septal defect 7;C3280785:Ventricular septal defect 3;C3280795:Hypoplastic left heart syndrome 2 Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.P283Q variant (also known as c.848C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 848. The proline at codon 283 is replaced by glutamine, an amino acid with similar properties. This alteration has been reported in individuals with ventricular septal defect, patent ductus arteriosus and aortic stenosis (Peng T et al. Genetica, 2010 Dec;138:1231-40; Abou Hassan OK et al. Sci Rep. 2015 Mar;5:8848). This variant was also reported in one individual from a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Mazzarotto F et al. Circulation, 2020 02;141:387-398). This variant has also been detected in congenital hypothyroidism cohorts, where some cases had additional genetic variants also detected (Fu C et al. Clin. Chim. Acta, 2019 Feb;489:103-108; Wang F et al. Front Endocrinol (Lausanne), 2020 Apr;11:237). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at