Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_000352.6(ABCC8):c.4105G>T(p.Ala1369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,778 control chromosomes in the GnomAD database, including 341,651 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
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]
In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6
BP4
Computational evidence support a benign effect (MetaRNN=1.2142411E-6).
BP6
Variant 11-17396930-C-A is Benign according to our data. Variant chr11-17396930-C-A is described in ClinVar as [Benign]. Clinvar id is 157699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17396930-C-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.
Review Status: criteria provided, single submitter
Collection Method: not provided
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Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Apr 12, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Aug 09, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is associated with the following publications: (PMID: 28411266, 25955821, 26551672, 27398621, 11117432, 22209866, 17823772, 25143473, 22187380, 19587354) -
not specified Benign:3
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Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 12, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Type 2 diabetes mellitus Benign:1
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: research
Mutations in this gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation have a better response to sulfonylureas. It doesn't cause any sensitivity toward mild hypoglycemia, an adverse effect of Sulfonylurea treatment. -
Hereditary hyperinsulinism Benign:1
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Leucine-induced hypoglycemia Benign:1
Jul 01, 2021
Pars Genome Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hyperinsulinism, Dominant/Recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Diabetes mellitus, transient neonatal, 2 Benign:1
Jul 01, 2021
Pars Genome Lab
Significance: Benign
Review Status: criteria provided, single submitter