11-5226954-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5
The NM_000518.5(HBB):āc.68A>Cā(p.Glu23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E23G) has been classified as Likely benign.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251294Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135798
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461520Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727102
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74354
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 10, 2024 | The Hb G-Coushatta variant (HBB: c.68A>C; p.Glu23Ala, also known as Glu22Ala when numbered from the mature protein, rs33936254, HbVar ID: 266) is reported in the heterozygous state in asymptomatic individuals (Blackwell 1967, HbVar database and references therein), and does not exacerbate clinical or hematological symptoms when found in trans to a pathogenic HBB variant (Koseler 2013, Perera 2015). The Hb G-Coushatta variant is reported in ClinVar (Variation ID: 15171), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 23 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.566). Based on available information, the Hb G-Coushatta variant is considered to be likely benign. REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Blackwell R et al. Hemoglobin variants in Koreans: hemoglobin G Taegu. Science. 1967 158(3804):1056-7. Koseler A et al. Molecular studies on the origin of the Hb G-Coushatta mutation in Denizli province of Turkey. Biochem Genet. 2013 51(1-2):71-5. Perera PS et al. Rare hemoglobin variants: Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in Sri Lankan families. Hemoglobin. 2015;39(1):62-5. - |
Pathogenic, flagged submission | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 19, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb G-Coushatta; This variant is associated with the following publications: (PMID: 23001606, 9048934, 34426522, 6033745, 29717566, 31553106, 19429541, 25572187, 6021187, 3115700, 18619001, 23806067, 5658717, 30568544, 34766575, 5791015, 31300739, 37188672, 14081243, 721611, 2703366, 28865746, 10081986) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 15, 2024 | The HBB c.68A>C (p.Glu23Ala) variant has been reported in the published literature in individuals, both heterozygous and homozygous, with normal clinical presentation ((HbVar http://globin.bx.psu.edu/, PMID: 27408413 (2016), and Ann Clin Case Rep (2017) 2:1353). The variant has also been reported in individuals with beta thalassemia and/or hemoglobin disorders (PMIDs: 23001606 (2013), 25849334 (2015), 37188672 (2023), and Quest internal patients). The frequency of this variant in the general population, 0.000008 (2/251294 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 21, 2025 | Variant summary: HBB c.68A>C (p.Glu23Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 676170 control chromosomes (gnomAD and publications). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (8.4e-05 vs 0.011), allowing no conclusion about variant significance. c.68A>C has been reported in the literature in healthy Native American, East Asian, Turkish, Egyptian, and Sri Lankan individuals in the heterozygous or homozygous state, suggesting that the variant is benign (e.g. Schneider_1964, Ohba_1978, Cao_1987, Li_1990, Hergersberg_2008, HbVar database). It has also been found to co-occur in cis and in trans with pathogenic beta-thalassemia variants (e.g. c.93-21G>A, IVS-1-1, G>A, and IVS-I-5) in patients, however in these cases it was believed to have little to no clinical impact (e.g. Hergersberg_2008, Koseler_2013, Perera_2015) . These data indicate that the variant is unlikely to be associated with disease. Additionally, a functional study has shown the variant to have normal oxygen equilibrium characteristics, and heat denaturation and isopropanol tests on hemolysates did not reveal instability of the hemoglobin, suggesting that the variant has a neutral effect on protein function (Ohba_1978). The following publications have been ascertained in the context of this evaluation (PMID: 18523401, 5791015, 5658717, 3115700, 2703366, 9048934, 19429541, 18619001, 6859036, 23001606, 2265836, 10081986, 23806067, 721611, 25572187, 18403562, 31553106, 14081243, 37188672, 27265760). ClinVar contains an entry for this variant (Variation ID: 15171). Based on the evidence outlined above, the variant was classified as likely benign. - |
beta Thalassemia Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
HEMOGLOBIN G (COUSHATTA) Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
HEMOGLOBIN G (HSIN-CHU) Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
HEMOGLOBIN G (TAEGU) Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
HEMOGLOBIN G (SASKATOON) Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at