rs587783168

Variant names:

• chr11-17408375-T-C
• rs2106865
• NM_000352.6:c.2820+17A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-17408375-T-C
• chr11-17408375-T-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000352.6(ABCC8):​c.2820+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,609,408 control chromosomes in the GnomAD database, including 304,157 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 0.62 (29149 hom., cov: 30)
  • Exomes 𝑓: 0.61 (275008 hom.)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.585
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-17408375-T-C is Benign according to our data. Variant chr11-17408375-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157694.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.2820+17A>G		intron_variant	Intron 23 of 38	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.2820+17A>G		intron_variant	Intron 23 of 38	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93620 AN: 151644 Hom.: 29135 Cov.: 30

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.692

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.635

GnomAD2 exomes AF: 0.616 AC: 153601 AN: 249280 AF XY: 0.606

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.746

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.612 AC: 891559 AN: 1457646 Hom.: 275008 Cov.: 35 AF XY: 0.608 AC XY: 440756 AN XY: 725276

African (AFR) AF: 0.618 AC: 20597 AN: 33308

American (AMR) AF: 0.696 AC: 30961 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 17189 AN: 26084

East Asian (EAS) AF: 0.715 AC: 28351 AN: 39670

South Asian (SAS) AF: 0.468 AC: 40282 AN: 86036

European-Finnish (FIN) AF: 0.529 AC: 27764 AN: 52514

Middle Eastern (MID) AF: 0.621 AC: 3180 AN: 5120

European-Non Finnish (NFE) AF: 0.618 AC: 685645 AN: 1110228

Other (OTH) AF: 0.625 AC: 37590 AN: 60190

GnomAD4 genome AF: 0.617 AC: 93692 AN: 151762 Hom.: 29149 Cov.: 30 AF XY: 0.609 AC XY: 45198 AN XY: 74170

African (AFR) AF: 0.615 AC: 25421 AN: 41348

American (AMR) AF: 0.649 AC: 9922 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2306 AN: 3466

East Asian (EAS) AF: 0.723 AC: 3698 AN: 5116

South Asian (SAS) AF: 0.476 AC: 2289 AN: 4812

European-Finnish (FIN) AF: 0.524 AC: 5541 AN: 10566

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.624 AC: 42317 AN: 67866

Other (OTH) AF: 0.634 AC: 1339 AN: 2112

Alfa AF: 0.629 Hom.: 108799

Bravo AF: 0.634

Asia WGS AF: 0.563 AC: 1956 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

-

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

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs2106865) in MODY yet. -

Transitory neonatal diabetes mellitus Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs2106865) in neonatal diabetes yet. -

Leucine-induced hypoglycemia Benign:1

Jul 01, 2021

Pars Genome Lab

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

- -

Hyperinsulinemic hypoglycemia, familial, 1 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.5
DANN	Benign	0.76
PhyloP100		-0.58
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: rs2106865; hg19: chr11-17429922; COSMIC: COSV56847309; COSMIC: COSV56847309;