Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000352.6(ABCC8):c.3329+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,611,936 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar 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=-0.84).
BP6
Variant 11-17406616-G-A is Benign according to our data. Variant chr11-17406616-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17406616-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1929/152264) while in subpopulation NFE AF= 0.0186 (1263/68018). AF 95% confidence interval is 0.0177. There are 12 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Likely benign, criteria provided, single submitter
not provided
Breakthrough Genomics, Breakthrough Genomics
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Benign, criteria provided, single submitter
clinical testing
GeneDx
Feb 27, 2020
This variant is associated with the following publications: (PMID: 23652837) -
Benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 31, 2024
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Benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Nov 03, 2023
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Benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Sep 01, 2024
ABCC8: BP4, BS1, BS2 -
not specified Benign:4
Benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
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Benign, criteria provided, single submitter
clinical testing
Eurofins Ntd Llc (ga)
Jan 22, 2015
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Benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Sep 06, 2018
Variant summary: ABCC8 c.3329+6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 274898 control chromosomes in the gnomAD database, including 26 homozygotes. The observed variant frequency is approximately 557705.035 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Neonatal Diabetes Mellitus phenotype (2.1e-08), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, no assertion criteria provided
clinical testing
Genetic Services Laboratory, University of Chicago
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Mar 08, 2018
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. -
Diabetes mellitus, transient neonatal, 2 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Mar 08, 2018
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
Mar 08, 2018
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. -
Transitory neonatal diabetes mellitus Benign:1
Benign, criteria provided, single submitter
research
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
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Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. However, no sufficient evidence is found to ascertain the role of rs113873225 variant in Diabetes Mellitus yet. -