rs1554924035
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000352.6(ABCC8):โc.2202delโ(p.Ala736LeufsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: ๐ 0.0000066 ( 0 hom., cov: 32)
Exomes ๐: 6.8e-7 ( 0 hom. )
Consequence
ABCC8
NM_000352.6 frameshift
NM_000352.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -2.06
Genes affected
ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 11-17427068-CT-C is Pathogenic according to our data. Variant chr11-17427068-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555310.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_risk_allele=2, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.2202del | p.Ala736LeufsTer12 | frameshift_variant | 16/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.2202del | p.Ala736LeufsTer12 | frameshift_variant | 16/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461794Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727202
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:5Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 28, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2019 | Variant summary: ABCC8 c.2202delA (p.Ala736LeufsX12) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg.c.2506C>T (p.Arg836X), c.3574delG (p.Asp1192fsX16)). The variant was absent in 246134 control chromosomes (gnomAD) but has been reported in the literature in an individual affected with Congenital Hyperinsulinism (Kapoor_2013). This data indicates that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2023 | ClinVar contains an entry for this variant (Variation ID: 555310). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 23345197). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ala736Leufs*12) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36208030, 21989597, 32027066, 18981553, 32792356, 20685672, 27538677, 16613899, 16885549, 18025408, 23345197) - |
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 03, 2023 | - - |
Neonatal diabetes mellitus Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | May 27, 2024 | This variant is found to be a potent moderate impact, variant with a sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele. - |
Maturity onset diabetes mellitus in young Other:1
Uncertain risk allele, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | May 27, 2024 | This variant is found to be a potent moderate impact variant with a sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at