Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1
The NM_000352.6(ABCC8):c.2485C>T(p.Leu829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,609,174 control chromosomes in the GnomAD database, including 10,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L829L) has been classified as Likely 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]
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.42).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-17412737-G-A is Benign according to our data. Variant chr11-17412737-G-A is described in ClinVar as [Benign]. Clinvar id is 157691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17412737-G-A is described in Lovd as [Benign].
BP7
?
BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=3.04 with no splicing effect.
BA1
?
BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter
clinical testing
Pars Genome Lab
Jul 01, 2021
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not specified Benign:2
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
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Likely benign, no assertion criteria provided
clinical testing
Genetic Services Laboratory, University of Chicago
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Diabetes mellitus, transient neonatal, 2 Benign:2
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter
clinical testing
Pars Genome Lab
Jul 01, 2021
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not provided Benign:2
Benign, criteria provided, single submitter
clinical testing
GeneDx
Aug 17, 2018
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Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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Hereditary hyperinsulinism Benign:1
Benign, no assertion criteria provided
clinical testing
Natera, Inc.
Sep 16, 2020
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Neonatal hypoglycemia Benign:1
Benign, criteria provided, single submitter
research
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
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rs1805036 variant of ABCC8 gene is associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. -
Leucine-induced hypoglycemia Benign:1
Benign, criteria provided, single submitter
clinical testing
Pars Genome Lab
Jul 01, 2021
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Diabetes mellitus, permanent neonatal 3 Benign:1
Benign, criteria provided, single submitter
clinical testing
Pars Genome Lab
Jul 01, 2021
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Permanent neonatal diabetes mellitus Benign:1
Benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 13, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -