11-17397732-C-T

Variant names:

• chr11-17397732-C-T
• rs1799859
• NM_000352.6:c.3819G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000352.6(ABCC8):​c.3819G>A​(p.Arg1273Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,552 control chromosomes in the GnomAD database, including 76,946 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (14758 hom., cov: 33)
  • Exomes 𝑓: 0.28 (62188 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.348
• Publications: 54 publications found

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]

ABCC8 Gene-Disease associations (from GenCC):

• hyperinsulinemic hypoglycemia, familial, 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial hyperinsulinism

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• diabetes mellitus

  Inheritance: SD Classification: DEFINITIVE Submitted by: Ambry Genetics
• monogenic diabetes

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypoglycemia, leucine-induced

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• diabetes mellitus, transient neonatal, 2

  Inheritance: Unknown, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to SUR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.02).
• BP6: Variant 11-17397732-C-T is Benign according to our data. Variant chr11-17397732-C-T is described in ClinVar as Benign. ClinVar VariationId is 157698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.348 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000352.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	NM_000352.6	MANE Select	c.3819G>A	p.Arg1273Arg	synonymous	Exon 31 of 39	NP_000343.2
	ABCC8	NM_001351295.2		c.3885G>A	p.Arg1295Arg	synonymous	Exon 31 of 39	NP_001338224.1
	ABCC8	NM_001287174.3		c.3822G>A	p.Arg1274Arg	synonymous	Exon 31 of 39	NP_001274103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.3819G>A	p.Arg1273Arg	synonymous	Exon 31 of 39	ENSP00000374467.4
	ABCC8	ENST00000644772.1		c.3885G>A	p.Arg1295Arg	synonymous	Exon 31 of 39	ENSP00000494321.1
	ABCC8	ENST00000302539.9	TSL:5	c.3822G>A	p.Arg1274Arg	synonymous	Exon 31 of 39	ENSP00000303960.4

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58825 AN: 152050 Hom.: 14720 Cov.: 33

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0878

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.365

GnomAD2 exomes AF: 0.291 AC: 72932 AN: 250196 AF XY: 0.283

Gnomad AFR exome AF: 0.714

Gnomad AMR exome AF: 0.391

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0832

Gnomad FIN exome AF: 0.155

Gnomad NFE exome AF: 0.264

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.278 AC: 406876 AN: 1461384 Hom.: 62188 Cov.: 43 AF XY: 0.277 AC XY: 201664 AN XY: 727004

African (AFR) AF: 0.726 AC: 24301 AN: 33478

American (AMR) AF: 0.391 AC: 17468 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 6661 AN: 26128

East Asian (EAS) AF: 0.101 AC: 4018 AN: 39700

South Asian (SAS) AF: 0.298 AC: 25704 AN: 86258

European-Finnish (FIN) AF: 0.159 AC: 8453 AN: 53034

Middle Eastern (MID) AF: 0.401 AC: 2315 AN: 5766

European-Non Finnish (NFE) AF: 0.270 AC: 300414 AN: 1111932

Other (OTH) AF: 0.290 AC: 17542 AN: 60386

GnomAD4 genome AF: 0.387 AC: 58918 AN: 152168 Hom.: 14758 Cov.: 33 AF XY: 0.379 AC XY: 28230 AN XY: 74398

African (AFR) AF: 0.704 AC: 29244 AN: 41514

American (AMR) AF: 0.400 AC: 6113 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3470

East Asian (EAS) AF: 0.0882 AC: 456 AN: 5172

South Asian (SAS) AF: 0.295 AC: 1426 AN: 4830

European-Finnish (FIN) AF: 0.155 AC: 1641 AN: 10606

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18140 AN: 67968

Other (OTH) AF: 0.361 AC: 761 AN: 2110

Alfa AF: 0.305 Hom.: 35894

Bravo AF: 0.417

Asia WGS AF: 0.230 AC: 805 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:3

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9799081, 22533711, 10857971, 18758683)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperinsulinemic hypoglycemia, familial, 1 Benign:2

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Type 2 diabetes mellitus Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. rs1799859 of ABCC8 gene is associated with Hb1Ac levels and its genotype might impact the Sulfonylurea treatment reponse.

Hereditary hyperinsulinism Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Leucine-induced hypoglycemia Benign:1

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hyperinsulinism, Dominant/Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diabetes mellitus, transient neonatal, 2 Benign:1

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diabetes mellitus, permanent neonatal 3 Benign:1

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Permanent neonatal diabetes mellitus Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Transient Neonatal Diabetes, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.9
DANN	Benign	0.68
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799859; hg19: chr11-17419279; COSMIC: COSV56850014; COSMIC: COSV56850014;