chr11-17460613-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000352.6(ABCC8):c.886G>A(p.Gly296Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,844 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 (★★).
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249738Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135254
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1460640Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6AN XY: 726692
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: The variant, ABCC8 c.886G>A (p.Gly296Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 277752 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.886G>A has been reported in the literature in individuals affected with Neonatal Diabetes Mellitus/diabetes mellitus of infancy (Cao_2016, Lin_2012). At-least one of these reports included an individual with Transient Neonatal Diabetes Mellitus (subtype T, Cao_2016) in whom the variant was inherited from the mother whose clinical status was not provided. These reports do not provide unequivocal conclusions about association of the variant with the disease. The variant was found to be causative to NDM in a compound heterozygous state (Lin_2012). The authors reported a recessive contribution of this variant in compound heterozygosity as manifesting in increased K-ATP channel conductance. At least one publication reports experimental evidence evaluating an impact on protein function (Lin_2012), however, this does not allow convincing conclusions about the variant effect under the presumed autosomal dominant mode of inheritance of NDM due to gain of function mutations in ABCC8. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least three new reports indicating its presence in individuals diagnosed with NDM or a related diabetic phenotype have emerged since its original classification. Based on the evidence outlined above, until additional functional impact and unequivocal co-segregation with disease in additional families/individuals with NDM is obtainedthe variant was classified as uncertain significance. -
Hereditary hyperinsulinism Uncertain:1
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Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 Uncertain:1
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Monogenic diabetes Uncertain:1
The p.Gly296Arg variant in ABCC8 has been reported in 1 Chinese and 1 Pakistan individuals, in the heterozygous or compound heterozygous state, with Monogenic Diabetes (PMID: 22562119, 26839896), and has been identified in 0.004013% (1/24920) of African chromosomes, 0.003267% (1/30610) of South Asian chromosomes, and 0.001555% (2/128636) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148529020). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and a likely pathogenic variant in ClinVar (Variation ID: 35624). In vitro functional studies provide some evidence that the p.Gly296Arg variant may slightly increase protein activity (PMID: 22562119). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the L0 domain, which has been associated with changes in the K-ATP channel of the protein and diabetes (PMID: 22562119). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PM1_Supporting (Richards 2015). -
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1
NM_000352.3(ABCC8):c.886G>A(G296R) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. G296R has been observed in cases with relevant disease (PMID: 22562119, 26839896). Functional assessments of this variant are available in the literature (PMID: 22562119). G296R has been observed in population frequency databases (gnomAD: AFR 0.004%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.886G>A(G296R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at