rs1799857

Positions:

• chr11-17430945-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000389817.8(ABCC8):​c.1686C>T​(p.His562=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 1,613,774 control chromosomes in the GnomAD database, including 161,862 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 0.44 (15076 hom., cov: 34)
  • Exomes 𝑓: 0.45 (146786 hom.)
• Consequence: ABCC8 ENST00000389817.8 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: -0.576

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-17430945-G-A is Benign according to our data. Variant chr11-17430945-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157684.We mark this variant Likely_benign, oryginal submissions are: {Benign=11, Uncertain_significance=1}. Variant chr11-17430945-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.576 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.1686C>T	p.His562=	synonymous_variant	12/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.1686C>T	p.His562=	synonymous_variant	12/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67148 AN: 152074 Hom.: 15054 Cov.: 34

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.380

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.428

GnomAD3 exomes AF: 0.422 AC: 105720 AN: 250612 Hom.: 22936 AF XY: 0.429 AC XY: 58091 AN XY: 135458

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.504

Gnomad FIN exome AF: 0.413

Gnomad NFE exome AF: 0.448

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.446 AC: 651709 AN: 1461582 Hom.: 146786 Cov.: 58 AF XY: 0.447 AC XY: 325076 AN XY: 727054

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.320

Gnomad4 ASJ exome AF: 0.445

Gnomad4 EAS exome AF: 0.309

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.411

Gnomad4 NFE exome AF: 0.453

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.442 AC: 67218 AN: 152192 Hom.: 15076 Cov.: 34 AF XY: 0.439 AC XY: 32704 AN XY: 74414

Gnomad4 AFR AF: 0.480

Gnomad4 AMR AF: 0.380

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.300

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.430

Alfa AF: 0.445 Hom.: 21849

Bravo AF: 0.440

Asia WGS AF: 0.442 AC: 1537 AN: 3478

EpiCase AF: 0.443

EpiControl AF: 0.446

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 09, 2021	- -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Diabetes mellitus, transient neonatal, 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Cerebral edema Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are generally associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. However, there is insufficient data to support the role of rs1799857 in Diabetes Mellitus. -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Leucine-induced hypoglycemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Diabetes mellitus, permanent neonatal 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Permanent neonatal diabetes mellitus 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.4
DANN	Benign	0.82

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: rs1799857; hg19: chr11-17452492; COSMIC: COSV56850686; COSMIC: COSV56850686;