5-173233062-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 ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161G) has been classified 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.482G>C | p.Arg161Pro | missense_variant | 2/2 | ENST00000329198.5 | |
NKX2-5 | NM_001166175.2 | c.*435G>C | 3_prime_UTR_variant | 2/2 | |||
NKX2-5 | NM_001166176.2 | c.*281G>C | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NKX2-5 | ENST00000329198.5 | c.482G>C | p.Arg161Pro | missense_variant | 2/2 | 1 | NM_004387.4 | P1 | |
NKX2-5 | ENST00000424406.2 | c.*435G>C | 3_prime_UTR_variant | 2/2 | 1 | ||||
NKX2-5 | ENST00000521848.1 | c.*281G>C | 3_prime_UTR_variant | 2/2 | 2 |
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
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2006 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2023 | 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