11-17408375-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -0.585

Publications

17 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
diabetes mellitus, permanent neonatal 3
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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
diabetes mellitus, transient neonatal, 2
Inheritance: AD, Unknown Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), 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: Genomics England PanelApp, Orphanet
permanent neonatal diabetes mellitus
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
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=-0.79).

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ABCC8	NM_000352.6	MANE Select	c.2820+17A>G	intron	N/A	NP_000343.2	Q09428-1
ABCC8	NM_001351295.2		c.2886+17A>G	intron	N/A	NP_001338224.1	A0A2R8Y4V0
ABCC8	NM_001287174.3		c.2823+17A>G	intron	N/A	NP_001274103.1	Q09428-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.2820+17A>G	intron	N/A	ENSP00000374467.4	Q09428-1
ABCC8	ENST00000644772.1		c.2886+17A>G	intron	N/A	ENSP00000494321.1	A0A2R8Y4V0
ABCC8	ENST00000302539.9	TSL:5	c.2823+17A>G	intron	N/A	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes

AF:

0.617

AC:

93620

AN:

151644

Hom.:

29135

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.608

AC XY:

440756

AN XY:

725276

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

16692

33384

50077

66769

83461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18346

36692

55038

73384

91730

<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:

0.617

AC:

93692

AN:

151762

Hom.:

29149

Cov.:

AF XY:

0.609

AC XY:

45198

AN XY:

74170

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1750

3500

5251

7001

8751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

774

1548

2322

3096

3870

<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:

0.629

Hom.:

108799

Bravo

AF:

0.634

Asia WGS

AF:

0.563

AC:

1956

AN:

3476

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Diabetes mellitus, permanent neonatal 3 (1)

Diabetes mellitus, transient neonatal, 2 (1)

Hyperinsulinemic hypoglycemia, familial, 1 (1)

Leucine-induced hypoglycemia (1)

Maturity-onset diabetes of the young (1)

Transitory neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.5

(source)

DANN

Benign

0.76

PhyloP100

-0.58

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over