chr11-17448511-AG-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP6_Very_Strong
The NM_000352.6(ABCC8):c.1332+4delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000352.6 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00121 AC: 184AN: 152092Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000970 AC: 244AN: 251448Hom.: 0 AF XY: 0.000920 AC XY: 125AN XY: 135896
GnomAD4 exome AF: 0.00129 AC: 1878AN: 1461464Hom.: 0 Cov.: 30 AF XY: 0.00124 AC XY: 900AN XY: 727066
GnomAD4 genome AF: 0.00121 AC: 184AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93AN XY: 74392
ClinVar
Submissions by phenotype
not provided Benign:4
This variant is associated with the following publications: (PMID: 16357843, 33410562) -
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not specified Benign:1
Variant summary: ABCC8 c.1332+4delC alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. This is consistent with functional studies using a minigene assay revealing no impact on splicing (Saint-Martin_2021). The variant allele was found at a frequency of 0.00097 in 251448 control chromosomes, predominantly at a frequency of 0.0016 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism, allowing no conclusion about variant significance. c.1332+4delC has been reported in the literature in individuals affected with Congenital Hyperinsulinism or Maturity-onset diabetes of the young (Suchi_2006, Saint-Martin_2021, Graff_2021). However, in some cases an alternative cause of disease was identified suggesting a benign role for this variant (Graff_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34032641, 27913849, 33410562, 16357843). ClinVar contains an entry for this variant (Variation ID: 157682). Based on the evidence outlined above, the variant was classified as likely benign. -
Inborn genetic diseases Benign:1
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. -
Hyperinsulinism, Dominant/Recessive Benign:1
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Hyperinsulinemic hypoglycemia, familial, 1 Benign:1
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Transient Neonatal Diabetes, Dominant Benign:1
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Permanent neonatal diabetes mellitus Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at