chr11-17461663-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000352.6(ABCC8):c.742C>T(p.Arg248*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000118 in 1,614,106 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000352.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135918
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727248
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74346
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2
Variant summary: ABCC8 c.742C>T (p.Arg248X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 246258 control chromosomes (gnomAD). c.742C>T has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism (Del Roio Liberatore_2015, Calabria_2012, Sandal_2009, FernndezMarmiesse_2006, Aguilar-Bryan_1999). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The p.Arg248Ter variant in ABCC8 has been reported in 10 individuals with hyperinsulinemic hypoglycemia (PMID: 10204114, 10828824, 16429405, 19475716, 23345197, 18767144, 20685672, 22855730, 27188453, 25972930, 30462810), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs72559730). 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: 585351) and has been interpreted as pathogenic by Athena Diagnostics Inc, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Invitae, and Natera (Inc.) and as likely pathogenic by Fulgent Genetics. Of the 10 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic/likely pathogenic variant in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg248Ter variant is pathogenic (Variation ID: 370210; PMID: 16429405, 20685672,22855730). This nonsense variant leads to a premature termination codon at position 248, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_strong, PM2_supporting (Richards 2015). -
not provided Pathogenic:2
This variant is present in population databases (rs72559730, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg248*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This premature translational stop signal has been observed in individual(s) with ABCC8-related conditions (PMID: 25972930, 27188453, 30191644, 30462810). 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 create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 585351). -
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Type 2 diabetes mellitus Pathogenic:1
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Hereditary hyperinsulinism Pathogenic: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 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at