rs886041392
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000352.6(ABCC8):c.3130_3149del(p.Thr1044LeufsTer63) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T1044T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000352.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.3130_3149del | p.Thr1044LeufsTer63 | frameshift_variant | 25/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.3130_3149del | p.Thr1044LeufsTer63 | frameshift_variant | 25/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152262Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250882Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135634
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461768Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727192
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74398
ClinVar
Submissions by phenotype
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Aug 16, 2023 | The p.Thr1044Leufs variant in ABCC8 has been previously reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 11395395, 20685672), and has been identified in 0.002% (2/113358) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs886041392). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 280115) and has been interpreted as likely pathogenic/pathogenic by Invitae, Rady Children's Institute for Genomic Medicine (Rady Children's Hospital San Diego), GeneDx, and Counsyl. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Thr1044Leufs variant is pathogenic (PMID: 11395395). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1044 and leads to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3 (Richards 2015). - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | May 01, 2018 | This variant has been previously reported in individuals with congenital hyperinsulism or familial hyperinsulinemic hypoglycemia-1 (HHF1) (MIM: 256450). It has been previously classified as pathogenic for congenital hyperinsulinism in ClinVar (rs886041392, https://www.ncbi.nlm.nih.gov/clinvar/variation/280115/) and HGMD (CD016051). This variant is present in gnomAD at 0.00081% (2/245734) and thus is presumed to be rare. This variant is predicted to create a frameshift in the protein coding sequence, leading to a truncated protein with reduced protein function. Based on the combined evidence, the c.3130_3149del20 p.Thr1044LeufsTer63 variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 18, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2018 | The c.3130_3149del20 pathogenic variant in the ABCC8 gene has been reported previously in the heterozygous state, as well as the compound heterozygous state, in association with congenital hyperinsulinism (Fournet et al., 2001; Bellanne-Chantelot et al., 2010). The c.3130_3149del20 variant causes a frameshift starting with codon Threonine 1044, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 63 of the new reading frame, denoted p.Thr1044LeufsX63. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.3130_3149del20 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.3130_3149del20 as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | This sequence change creates a premature translational stop signal (p.Thr1044Leufs*63) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (no rsID available, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 11395395). This variant has been reported in individual(s) with autosomal dominant familial hyperinsulinism (PMID: 24401662, 32928245); however, the role of the variant in this condition is currently unclear. This variant is also known as c.3133_3152del. ClinVar contains an entry for this variant (Variation ID: 280115). For these reasons, this variant has been classified as Pathogenic. - |
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at