rs67254669

chr11-17448596-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000352.6(ABCC8):c.1252T>C(p.Cys418Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,614,244 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (1 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:3
• Conservation: PhyloP100: 2.87

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08235839).
• BP6: Variant 11-17448596-A-G is Benign according to our data. Variant chr11-17448596-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210067.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=1, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.1252T>C	p.Cys418Arg	missense_variant	8/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.1252T>C	p.Cys418Arg	missense_variant	8/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000688 AC: 173 AN: 251488 Hom.: 0 AF XY: 0.000750 AC XY: 102 AN XY: 135916

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000946 AC: 1383 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000985 AC XY: 716 AN XY: 727246

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74488

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.000578

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000642 AC: 78

EpiCase AF: 0.000654

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 418 of the ABCC8 protein (p.Cys418Arg). This variant is present in population databases (rs67254669, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and/or clinical features of ABCC8-related conditions (PMID: 22210575, 23345197, 30447144). ClinVar contains an entry for this variant (Variation ID: 210067). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2022	Observed in the heterozygous state in unrelated probands with neonatal diabetes, type 2 diabetes, hyperinsulinism, and suspected MODY in published literature (Kapoor et al., 2013; Riveline et al., 2012; Snider et al., 2013; zdemir et al., 2018; Ates et al., 2021), however, familial segregation information was not provided; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 2165579, 17539904, 22210575, 16380471, 10204114, 30447144, 32640185, 32763092, 23275527, 30297969, 23345197, 32041611, 34426522, 34462253, 33108363) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 22, 2022	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. Computational tools disagree on the variant's effect on normal protein function. -

Type 2 diabetes mellitus Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 15, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 28, 2021	- -

Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 13, 2022	Variant summary: ABCC8 c.1252T>C (p.Cys418Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251488 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00069 vs 0.0034), allowing no conclusion about variant significance. c.1252T>C has been reported in patients with congenital hyperinsulinism (CHI) in the heterozygous state, without strong evidence for causality (e.g. Aguilar-Bryan_1999, Kapoor_2013, Snider_2013). An additional occurrence was reported in a patient with atypical Fanconi-Bickel syndrome (hyperinsulinemia compared to the typical diminished insulin secretion), who also carried known pathogenic mutations in SLC2A2; the mother was also a carrier of the variant and had no history of hypoglycemia therefore, allowing no conclusions about variant significance (Hoffman_2007). Additionally, p.C418R was reported as maternally inherited in a case of focal hyperinsulinemia (Otonkoski_2006). In this patient, the authors concluded that since the variant was apparently not expressed within the focal lesion it is likely not of functional importance. Lastly, the variant was detected in patients with MODY (Ozdemir_2018, Ates_2021, Demirci_2021), while it was also reported in association with type 2 diabetes (Riveline_2012, Mahajan_2018, Kim_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and nine ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 23, 2020	- -

Diabetes mellitus, transient neonatal, 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense c.1252T>C (p.Cys418Arg) variant in ABCC8 gene has been reported previously in an individuals affected with ABCC8-related diabetes (Kapoor et al. 2013; Ateş et al. 2021). The p.Cys418Arg variant is reported with an allele frequency of 0.07% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Benign / Likely Benign / Uncertain Significance. The amino acid change p.Cys418Arg in ABCC8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 418 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1833104:Permanent neonatal diabetes mellitus;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary hyperinsulinism Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Diabetes mellitus, permanent neonatal 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pars Genome Lab

May 18, 2021

- -

Hypoglycemia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

- -

ABCC8-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2023

The ABCC8 c.1252T>C variant is predicted to result in the amino acid substitution p.Cys418Arg. This variant has been reported in both adult-onset diabetes and congenital hyperinsulinism, but its pathogenicity was not fully established (Riveline et al. 2012. PubMed ID: 22210575; Otonkoski et al. 2006. PubMed ID: 16380471; Kapoor et al. 2013. PubMed ID: 23345197). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17470143-A-G), which may be too common to be a primary cause of disease. Although we suspect that this variant may possibly be benign, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Permanent neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.056	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
Polyphen		0.14	.;.;B;.;.;.;.;.
Vest4		0.96, 0.96
MVP		0.87
MPC		0.69
ClinPred		0.027	T
GERP RS		4.6
Varity_R		0.92
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs67254669; hg19: chr11-17470143;