chr11-17427963-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000352.6(ABCC8):c.2041-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,611,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000352.6 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000205 AC: 5AN: 244490Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132088
GnomAD4 exome AF: 0.0000555 AC: 81AN: 1458954Hom.: 0 Cov.: 31 AF XY: 0.0000593 AC XY: 43AN XY: 725496
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:3
The c.2041-21G>A variant in ABCC8 has been reported in 11 individuals with hyperinsulinemic hypoglycemia (PMID: 31464105, 25765446, 24401662, 15807877, 34927408, 27908292, 26268944, 23275527), and has been identified in 0.009% (2/24340) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746714109). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 553929) and has been interpreted as likely pathogenic by Counsyl and Mendelics and as pathogenic by Invitae. Of the 11 affected individuals, at least 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the c.2041-21G>A variant is pathogenic (PMID: 27908292, 23275527). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very-strong, PP3, PM2_supporting (Richards 2015). -
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Type 2 diabetes mellitus Pathogenic:1
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Inborn genetic diseases Pathogenic:1
The c.2041-21G>A intronic alteration consists of a G to A substitution 21 nucleotides before coding exon 15 of the ABCC8 gene. _x000D_ _x000D_ Based on the available evidence, the ABCC8 c.2041-21G>A alteration is classified as pathogenic for familial hyperinsulinemic hypoglycemia; however, it is unlikely to be causative of ABCC8-related diabetes mellitus. Based on data from gnomAD, the A allele has an overall frequency of 0.003% (7/275874) total alleles studied. The highest observed frequency was 0.008% (2/24340) of African alleles. This variant has been reported heterozygous, compound heterozygous, and homozygous in individuals with congenital hyperinsulinism and hypoglycemia (Ohkubo, 2005; Snider, 2013; Mohnike, 2014; Senniappan, 2015; Salomon-Estebanez, 2016; Razzaghy-Azar, 2022). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -
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 Pathogenic:1
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not provided Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 553929). This variant has been observed in individual(s) with clinical features of ABCC8-related conditions (PMID: 15807877, 24401662, 25765446, 26268944). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs746714109, gnomAD 0.009%). This sequence change falls in intron 14 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at