NM_000352.6:c.2117-3C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000352.6(ABCC8):c.2117-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,608,952 control chromosomes in the GnomAD database, including 148,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 12005 hom., cov: 31)

Exomes 𝑓: 0.43 ( 136397 hom. )

Consequence

ABCC8
NM_000352.6 splice_region, intron

Scores

Splicing: ADA: 0.1129

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: 2.82

Publications

63 publications found

Variant links:

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)

ABCC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.23).

BP6

Variant 11-17427157-G-A is Benign according to our data. Variant chr11-17427157-G-A is described in ClinVar as Benign. ClinVar VariationId is 157688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.2117-3C>T		splice_region_variant, intron_variant	Intron 15 of 38	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.2117-3C>T		splice_region_variant, intron_variant	Intron 15 of 38	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.372

AC:

56513

AN:

151924

Hom.:

11999

Cov.:

show subpopulations

Gnomad AFR

AF:

0.167

Gnomad AMI

AF:

0.546

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.455

Gnomad EAS

AF:

0.566

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.438

Gnomad OTH

AF:

0.406

GnomAD2 exomes

AF:

0.440

AC:

108736

AN:

246958

AF XY:

0.433

show subpopulations

Gnomad AFR exome

AF:

0.160

Gnomad AMR exome

AF:

0.609

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.596

Gnomad FIN exome

AF:

0.431

Gnomad NFE exome

AF:

0.436

Gnomad OTH exome

AF:

0.428

GnomAD4 exome

AF:

0.427

AC:

622485

AN:

1456910

Hom.:

136397

Cov.:

AF XY:

0.425

AC XY:

308010

AN XY:

724320

show subpopulations

African (AFR)

AF:

0.158

AC:

5295

AN:

33428

American (AMR)

AF:

0.597

AC:

26467

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.457

AC:

11888

AN:

26012

East Asian (EAS)

AF:

0.540

AC:

21346

AN:

39502

South Asian (SAS)

AF:

0.328

AC:

28159

AN:

85730

European-Finnish (FIN)

AF:

0.433

AC:

22833

AN:

52672

Middle Eastern (MID)

AF:

0.397

AC:

2281

AN:

5750

European-Non Finnish (NFE)

AF:

0.431

AC:

478352

AN:

1109296

Other (OTH)

AF:

0.430

AC:

25864

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

18483

36966

55450

73933

92416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14460

28920

43380

57840

72300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.372

AC:

56535

AN:

152042

Hom.:

12005

Cov.:

AF XY:

0.374

AC XY:

27762

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.167

AC:

6910

AN:

41488

American (AMR)

AF:

0.499

AC:

7624

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.455

AC:

1580

AN:

3472

East Asian (EAS)

AF:

0.565

AC:

2908

AN:

5148

South Asian (SAS)

AF:

0.346

AC:

1664

AN:

4814

European-Finnish (FIN)

AF:

0.436

AC:

4607

AN:

10556

Middle Eastern (MID)

AF:

0.442

AC:

130

AN:

294

European-Non Finnish (NFE)

AF:

0.438

AC:

29765

AN:

67974

Other (OTH)

AF:

0.404

AC:

850

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1676

3352

5029

6705

8381

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.425

Hom.:

25070

Bravo

AF:

0.373

Asia WGS

AF:

0.404

AC:

1409

AN:

3478

EpiCase

AF:

0.441

EpiControl

AF:

0.442

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 18, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26740944, 29469970, 16429405, 15807877, 8635661, 25525159, 22533711, 10333056, 10857971, 20079163) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2014

Eurofins Ntd Llc (ga)

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

- -

Diabetes mellitus, transient neonatal, 2

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 01, 2021

Pars Genome Lab

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 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

- -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3

Benign:1

May 04, 2022

Fulgent Genetics, Fulgent Genetics

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Type 2 diabetes mellitus

Other:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:association

Review Status:no assertion criteria provided

Collection Method:research

Mutations in this gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation have a better response to sulfonylureas. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.8

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.11

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over