chr5-173233062-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_004387.4(NKX2-5):āc.482G>Cā(p.Arg161Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,603,758 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 Uncertain significance (ā ā ).
Frequency
Consequence
NM_004387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.482G>C | p.Arg161Pro | missense_variant | Exon 2 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.*281G>C | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.*435G>C | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.482G>C | p.Arg161Pro | missense_variant | Exon 2 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406 | c.*435G>C | 3_prime_UTR_variant | Exon 2 of 2 | 1 | ENSP00000395378.2 | ||||
NKX2-5 | ENST00000521848 | c.*281G>C | 3_prime_UTR_variant | Exon 2 of 2 | 2 | ENSP00000427906.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000869 AC: 2AN: 230216Hom.: 0 AF XY: 0.0000160 AC XY: 2AN XY: 125214
GnomAD4 exome AF: 0.00000551 AC: 8AN: 1451422Hom.: 0 Cov.: 35 AF XY: 0.00000416 AC XY: 3AN XY: 721346
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74494
ClinVar
Submissions by phenotype
Hypothyroidism, congenital, nongoitrous, 5 Pathogenic:1
- -
Atrial septal defect 7 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 161 of the NKX2-5 protein (p.Arg161Pro). This variant is present in population databases (rs137852685, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of NKX2-5-related conditions (PMID: 16418214). ClinVar contains an entry for this variant (Variation ID: 9019). 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) has been performed at Invitae 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 NKX2-5 protein function. Experimental studies have shown that this missense change affects NKX2-5 function (PMID: 16418214). 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. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a patient with thyroid dysgenesis in published literature (Dentice et al., 2006); Functional studies showed that p.(R161P) results in reduced activity of reporter genes and impaired DNA binding of NKX2-5 compared to wild-type (Dentice et al., 2006); This variant is associated with the following publications: (PMID: 27013732, 27152669, 35328834, 16418214) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at