rs147623093
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2
The NM_000352.6(ABCC8):c.1707C>T(p.Ala569=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,614,228 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A569A) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.00083 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00076 ( 6 hom. )
Consequence
ABCC8
NM_000352.6 synonymous
NM_000352.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.196
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 Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.44).
BP6
Variant 11-17430924-G-A is Benign according to our data. Variant chr11-17430924-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210070.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=4, Benign=7}. Variant chr11-17430924-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-0.196 with no splicing effect.
BS2
High Homozygotes in GnomAdExome4 at 6 SD gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ABCC8 | NM_000352.6 | c.1707C>T | p.Ala569= | synonymous_variant | 12/39 | ENST00000389817.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ABCC8 | ENST00000389817.8 | c.1707C>T | p.Ala569= | synonymous_variant | 12/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes 0.000828 AC: 126AN: 152252Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00127 AC: 318AN: 251336Hom.: 2 AF XY: 0.00119 AC XY: 161AN XY: 135842
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GnomAD4 exome AF: 0.000759 AC: 1110AN: 1461858Hom.: 6 Cov.: 30 AF XY: 0.000752 AC XY: 547AN XY: 727230
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GnomAD4 genome 0.000827 AC: 126AN: 152370Hom.: 1 Cov.: 33 AF XY: 0.000913 AC XY: 68AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:11
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 04, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 18, 2018 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:2
| Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 25, 2018 | - - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 31, 2022 | Variant summary: ABCC8 c.1707C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 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 0.0013 in 251336 control chromosomes, predominantly at a frequency of 0.018 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. This frequency is approximately 5-fold the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Maturity onset diabetes mellitus in young Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs147623093) in MODY yet. - |
Permanent neonatal diabetes mellitus Uncertain:1
| Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Transitory neonatal diabetes mellitus Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs147623093) in neonatal diabetes yet. - |
Inborn genetic diseases Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 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
| 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. - |
Diabetes mellitus, permanent neonatal 3 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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