5-173232837-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_004387.4(NKX2-5):c.707C>A(p.Pro236His) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,611,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NKX2-5 | NM_004387.4 | c.707C>A | p.Pro236His | missense_variant | Exon 2 of 2 | ENST00000329198.5 | NP_004378.1 | |
NKX2-5 | NM_001166176.2 | c.*506C>A | 3_prime_UTR_variant | Exon 2 of 2 | NP_001159648.1 | |||
NKX2-5 | NM_001166175.2 | c.*660C>A | 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.707C>A | p.Pro236His | missense_variant | Exon 2 of 2 | 1 | NM_004387.4 | ENSP00000327758.4 | ||
NKX2-5 | ENST00000424406.2 | c.*660C>A | downstream_gene_variant | 1 | ENSP00000395378.2 | |||||
NKX2-5 | ENST00000521848.1 | c.*506C>A | downstream_gene_variant | 2 | ENSP00000427906.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152270Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000417 AC: 1AN: 239642Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131450
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459612Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 726036
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74400
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect with reduced transactivation within the Pbx/Nkx2-5/p15 regulatory module for spleen development (Koss et al., 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in a patient with isolated congenital asplenia and segregated with this phenotype in two relatives (Mahlaoui et al., 2011; Koss et al., 2012); This variant is associated with the following publications: (PMID: 20846672, 22560297) -
Familial isolated congenital asplenia Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.P236H variant (also known as c.707C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 707. The proline at codon 236 is replaced by histidine, an amino acid with similar properties. This variant has been detected in a kindred with isolated congenital asplenia and without know congenital heart disease. Functional studies from the same group indicated this variant may impair transactivation by NKX2-5 (Koss M et al. Dev Cell, 2012 May;22:913-26). This amino acid position is not well 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