rs1799854

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_000352.6(ABCC8):c.2117-3C>T variant causes a splice region, splice polypyrimidine tract, 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. 2/2 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.1129

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: 2.82

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.2117-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.2117-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000352.6	P4	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

GnomAD3 exomes

AF:

0.440

AC:

108736

AN:

246958

Hom.:

25627

AF XY:

0.433

AC XY:

57896

AN XY:

133576

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 SAS exome

AF:

0.325

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

Gnomad4 AFR exome

AF:

0.158

Gnomad4 AMR exome

AF:

0.597

Gnomad4 ASJ exome

AF:

0.457

Gnomad4 EAS exome

AF:

0.540

Gnomad4 SAS exome

AF:

0.328

Gnomad4 FIN exome

AF:

0.433

Gnomad4 NFE exome

AF:

0.431

Gnomad4 OTH exome

AF:

0.430

GnomAD4 genome

AF:

0.372

AC:

56535

AN:

152042

Hom.:

12005

Cov.:

AF XY:

0.374

AC XY:

27762

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.167

Gnomad4 AMR

AF:

0.499

Gnomad4 ASJ

AF:

0.455

Gnomad4 EAS

AF:

0.565

Gnomad4 SAS

AF:

0.346

Gnomad4 FIN

AF:

0.436

Gnomad4 NFE

AF:

0.438

Gnomad4 OTH

AF:

0.404

Alfa

AF:

0.437

Hom.:

19049

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:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2018	This variant is associated with the following publications: (PMID: 26740944, 29469970, 16429405, 15807877, 8635661, 25525159, 22533711, 10333056, 10857971, 20079163) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
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	Apr 27, 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. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

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

Apr 27, 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

Other:1

association, no assertion criteria provided

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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

Dann

Benign

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over