Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_000352.6(ABCC8):c.2277C>T(p.Thr759=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,610,186 control chromosomes in the GnomAD database, including 1,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T759T) 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]
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BP6
Variant 11-17415318-G-A is Benign according to our data. Variant chr11-17415318-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 157689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17415318-G-A is described in Lovd as [Benign]. Variant chr11-17415318-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.48 with no splicing effect.
BA1
GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0519 is higher than 0.05.
This variant is associated with the following publications: (PMID: 24768178, 22902787, 9075812, 25955821, 24959012, 22704848, 18758683, 18599530, 15842514, 15111507, 11246895, 31118371, 11289470) -
not specified Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Mar 27, 2013
- -
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
-
- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
May 24, 2022
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Hereditary hyperinsulinism Benign:1
Benign, no assertion criteria provided
clinical testing
Natera, Inc.
Sep 16, 2020
- -
Diabetes mellitus, transient neonatal, 2 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Permanent neonatal diabetes mellitus Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -