8-23702612-C-T
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001136271.3(NKX2-6):c.745G>A(p.Gly249Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000917 in 1,547,926 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_001136271.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000249 AC: 37AN: 148364Hom.: 2 AF XY: 0.000378 AC XY: 30AN XY: 79270
GnomAD4 exome AF: 0.0000996 AC: 139AN: 1395788Hom.: 4 Cov.: 32 AF XY: 0.000150 AC XY: 103AN XY: 688376
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74330
ClinVar
Submissions by phenotype
Conotruncal heart malformations Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 249 of the NKX2-6 protein (p.Gly249Arg). This variant is present in population databases (rs752427485, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NKX2-6-related conditions. ClinVar contains an entry for this variant (Variation ID: 534672). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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