rs1057516317
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000352.6(ABCC8):βc.3574delGβ(p.Asp1192fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,098 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
ABCC8
NM_000352.6 frameshift
NM_000352.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.91
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 18 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 11-17402736-TC-T is Pathogenic according to our data. Variant chr11-17402736-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727248
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Asp1192Metfs*16) 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 individuals with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 14692646, 30462810). This variant is also known as 3576delG. ClinVar contains an entry for this variant (Variation ID: 370210). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 02, 2023 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with either focal or diffuse congenital hyperinsulinism (CHI). - |
Familial hyperinsulinism Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2017 | Variant summary: The ABCC8 c.3574delG (p.Asp1192Metfs)(legacy names: c.3577delG and c.3576delG) variant results in a premature termination codon, predicted to cause a truncated or absent ABCC8 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 121604 control chromosomes. Multiple publications have cited the variant in compound heterozygote indivdiuals affected with Congenital Hyperinsulinisim. A clinical diagnostic laboratory classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic. - |
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2024 | - - |
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
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 22, 2024 | - - |
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2015 | - - |
Computational scores
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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