11-17395872-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000352.6(ABCC8):c.4178G>A(p.Arg1393His) variant causes a missense change. The variant allele was found at a frequency of 0.0000365 in 1,587,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000038 ( 0 hom. )
Consequence
ABCC8
NM_000352.6 missense
NM_000352.6 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 6.16
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 11-17395872-C-T is Pathogenic according to our data. Variant chr11-17395872-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446776.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.4178G>A | p.Arg1393His | missense_variant | 34/39 | ENST00000389817.8 | NP_000343.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.4178G>A | p.Arg1393His | missense_variant | 34/39 | 1 | NM_000352.6 | ENSP00000374467 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152104Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000385 AC: 8AN: 207710Hom.: 0 AF XY: 0.00000901 AC XY: 1AN XY: 110950
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GnomAD4 exome AF: 0.0000376 AC: 54AN: 1434990Hom.: 0 Cov.: 31 AF XY: 0.0000295 AC XY: 21AN XY: 710692
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152104Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74286
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 06, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 26, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 24, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1393 of the ABCC8 protein (p.Arg1393His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital hyperinsulinism (PMID: 9618169). This variant is also known as R1394H. ClinVar contains an entry for this variant (Variation ID: 446776). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840, 11457841, 17575084). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2022 | Reported in a patient with familial hyperinsulinism who also harbors an additional variant in the ABCC8 gene (Nestorowicz et al., 1998); Also known as p.R1394H (c.4181G>A); Published functional studies using transfected cells were not consistent in their results regarding the potential effect of this variant on channel function and protein trafficking (Shyng et al., 1998; Partridge et al., 2001; Yan et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9648840, 17575084, 32041611, 11457841, 17956278, 24399968, 14707124, 9618169, 23226049) - |
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Aug 16, 2023 | The p.Arg1393His variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 9648840, 9618169, 32041611) and has been identified in 0.008% (2/25832) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769279368). 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: 446776) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago), Natera Inc., and Athena Diagnostics Inc., and as a variant of uncertain significance by Myriad Women's Health Inc. 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.Arg1393His variant is pathogenic (Variation ID: 9088; PMID: 9648840). In vitro functional studies provide some evidence that the p.Arg1393His variant may impact protein function (PMID: 9648840, 11457841). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting, PS3_supporting (Richards 2015). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_000352.3(ABCC8):c.4178G>A(R1393H) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. R1393H has been observed in cases with relevant disease (PMID: 9618169). Functional assessments of this variant are available in the literature (PMID: 9648840, 11457841). R1393H has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.4178G>A(R1393H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Type 2 diabetes mellitus Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 20, 2023 | - - |
Hereditary hyperinsulinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Diabetes Institute, Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;D;D;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;.;D;D;.;.;.;.
Sift4G
Uncertain
.;.;D;D;.;.;.;.
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.99
MutPred
0.97
.;.;Loss of stability (P = 0.0487);.;.;.;Loss of stability (P = 0.0487);.;
MVP
0.95
MPC
2.0
ClinPred
D
GERP RS
Varity_R
gMVP
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