chr11-17395949-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000352.6(ABCC8):c.4120-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 1,561,592 control chromosomes in the GnomAD database, including 192 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 0.014 ( 35 hom., cov: 33)

Exomes 𝑓: 0.0069 ( 157 hom. )

Consequence

ABCC8
NM_000352.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.797

Publications

7 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 11-17395949-G-A is Benign according to our data. Variant chr11-17395949-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35612.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0141 (2143/152352) while in subpopulation AMR AF = 0.0292 (447/15312). AF 95% confidence interval is 0.027. There are 35 homozygotes in GnomAd4. There are 1065 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR,AD,Unknown,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.4120-19C>T		intron_variant	Intron 33 of 38	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.4120-19C>T		intron_variant	Intron 33 of 38	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2128

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0291

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0258

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0177

AC:

2943

AN:

165810

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.0509

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.0256

Gnomad FIN exome

AF:

0.000327

Gnomad NFE exome

AF:

0.00318

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.00687

AC:

9684

AN:

1409240

Hom.:

157

Cov.:

AF XY:

0.00727

AC XY:

5062

AN XY:

695900

show subpopulations

African (AFR)

AF:

0.0291

AC:

951

AN:

32674

American (AMR)

AF:

0.0483

AC:

1812

AN:

37486

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

263

AN:

25212

East Asian (EAS)

AF:

0.0309

AC:

1143

AN:

37034

South Asian (SAS)

AF:

0.0255

AC:

2045

AN:

80196

European-Finnish (FIN)

AF:

0.000325

AC:

AN:

49234

Middle Eastern (MID)

AF:

0.0239

AC:

136

AN:

5700

European-Non Finnish (NFE)

AF:

0.00243

AC:

2638

AN:

1083378

Other (OTH)

AF:

0.0117

AC:

680

AN:

58326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

678

1356

2033

2711

3389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<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:

0.0141

AC:

2143

AN:

152352

Hom.:

Cov.:

AF XY:

0.0143

AC XY:

1065

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0274

AC:

1139

AN:

41574

American (AMR)

AF:

0.0292

AC:

447

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.0260

AC:

135

AN:

5184

South Asian (SAS)

AF:

0.0236

AC:

114

AN:

4822

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00298

AC:

203

AN:

68040

Other (OTH)

AF:

0.0241

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0113

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16429405, 33410562, 27884173)

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCC8: BS1, BS2

Sep 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 16, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The ABCC8 c.4120-19C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 604/26462 control chromosomes (11 homozygotes) at a frequency of 0.0228252, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (2.1e-8), suggesting this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together and based on the prevalence in general population this variant is classified as Benign.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hyperinsulinemia

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 response to sulfonylureas. Although rs1800853 is prevalent in hyperinsulinemic hypoglycemia in infancy, sufficient evidence is not seen to demonstrate the association of this variant with neonatal diabetes or MODY.

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

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

-0.80

CADD

Benign

6.2

(source)

DANN

Benign

0.71

PhyloP100

0.80

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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