chr11-17443296-ATC-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000352.6(ABCC8):c.1347_1348del(p.Ile450SerfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
ABCC8
NM_000352.6 frameshift
NM_000352.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.50
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-17443296-ATC-A is Pathogenic according to our data. Variant chr11-17443296-ATC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558438.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_risk_allele=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.1347_1348del | p.Ile450SerfsTer44 | frameshift_variant | 9/39 | ENST00000389817.8 | NP_000343.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.1347_1348del | p.Ile450SerfsTer44 | frameshift_variant | 9/39 | 1 | NM_000352.6 | ENSP00000374467 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 07, 2020 | This sequence change is a two base pair deletion in exon 9, c.1347_1348del. This sequence change results in an amino acid frameshift and creates a premature stop codon 43 amino acids downstream of the change, p.Ile450Serfs*44. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ABCC8 protein with potentially abnormal function. This sequence change is absent from the large population databases such as ExAC and gnomAD. This sequence change has previously been described in a Diazoxide-responsive patient with CHI (PMID: 16429405). - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2023 | This sequence change creates a premature translational stop signal (p.Ile450Serfs*44) 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 variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ABCC8-related conditions (PMID: 16429405). ClinVar contains an entry for this variant (Variation ID: 558438). For these reasons, this variant has been classified as Pathogenic. - |
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 22, 2018 | - - |
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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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at