chr14-104770411-A-G
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_001382430.1(AKT1):c.1373T>C(p.Met458Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,611,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M458K) has been classified as Uncertain significance.
Frequency
Consequence
NM_001382430.1 missense
Scores
Clinical Significance
Conservation
Publications
- Proteus syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- Cowden diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cowden syndrome 6Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AKT1 | NM_001382430.1 | c.1373T>C | p.Met458Thr | missense_variant | Exon 15 of 15 | ENST00000649815.2 | NP_001369359.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000453 AC: 11AN: 242576 AF XY: 0.0000607 show subpopulations
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1459110Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 725692 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74358 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Cowden syndrome 6 Uncertain:1
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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 133454). This variant has not been reported in the literature in individuals affected with AKT1-related conditions. This variant is present in population databases (rs587778018, gnomAD 0.06%). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 458 of the AKT1 protein (p.Met458Thr). -
not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at