Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_000352.6(ABCC8):c.207T>C(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,814 control chromosomes in the GnomAD database, including 191,759 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 0.46 ( 16400 hom., cov: 32)

Exomes 𝑓: 0.49 ( 175359 hom. )

Consequence

ABCC8
NM_000352.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: -2.61

Publications

38 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 11-17474969-A-G is Benign according to our data. Variant chr11-17474969-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157687.

BP7

Synonymous conserved (PhyloP=-2.61 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.51 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	HGVSp	Effect	Exon Rank	Protein
ABCC8	NM_000352.6	MANE Select	c.207T>C	p.Pro69Pro	synonymous	Exon 2 of 39	NP_000343.2
ABCC8	NM_001351295.2		c.207T>C	p.Pro69Pro	synonymous	Exon 2 of 39	NP_001338224.1
ABCC8	NM_001287174.3		c.207T>C	p.Pro69Pro	synonymous	Exon 2 of 39	NP_001274103.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.207T>C	p.Pro69Pro	synonymous	Exon 2 of 39	ENSP00000374467.4
ABCC8	ENST00000612903.2	TSL:1	n.108T>C		non_coding_transcript_exon	Exon 2 of 3
ABCC8	ENST00000644772.1		c.207T>C	p.Pro69Pro	synonymous	Exon 2 of 39	ENSP00000494321.1

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69831

AN:

151940

Hom.:

16402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.545

Gnomad AMR

AF:

0.520

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.380

Gnomad SAS

AF:

0.465

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.646

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.512

GnomAD2 exomes

AF:

0.475

AC:

119354

AN:

251110

AF XY:

0.475

show subpopulations

Gnomad AFR exome

AF:

0.396

Gnomad AMR exome

AF:

0.565

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.363

Gnomad FIN exome

AF:

0.322

Gnomad NFE exome

AF:

0.502

Gnomad OTH exome

AF:

0.490

GnomAD4 exome

AF:

0.487

AC:

711716

AN:

1461760

Hom.:

175359

Cov.:

AF XY:

0.487

AC XY:

353913

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.402

AC:

13448

AN:

33478

American (AMR)

AF:

0.562

AC:

25123

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14180

AN:

26134

East Asian (EAS)

AF:

0.376

AC:

14941

AN:

39700

South Asian (SAS)

AF:

0.469

AC:

40433

AN:

86246

European-Finnish (FIN)

AF:

0.326

AC:

17417

AN:

53416

Middle Eastern (MID)

AF:

0.604

AC:

3484

AN:

5768

European-Non Finnish (NFE)

AF:

0.498

AC:

553287

AN:

1111926

Other (OTH)

AF:

0.487

AC:

29403

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

23956

47913

71869

95826

119782

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16056

32112

48168

64224

80280

<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:

0.459

AC:

69856

AN:

152054

Hom.:

16400

Cov.:

AF XY:

0.452

AC XY:

33561

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.402

AC:

16660

AN:

41466

American (AMR)

AF:

0.520

AC:

7944

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.553

AC:

1917

AN:

3468

East Asian (EAS)

AF:

0.381

AC:

1965

AN:

5160

South Asian (SAS)

AF:

0.464

AC:

2237

AN:

4818

European-Finnish (FIN)

AF:

0.317

AC:

3354

AN:

10578

Middle Eastern (MID)

AF:

0.650

AC:

191

AN:

294

European-Non Finnish (NFE)

AF:

0.501

AC:

34021

AN:

67966

Other (OTH)

AF:

0.508

AC:

1072

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1917

3833

5750

7666

9583

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

648

1296

1944

2592

3240

<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:

0.489

Hom.:

52877

Bravo

AF:

0.474

Asia WGS

AF:

0.393

AC:

1365

AN:

3478

EpiCase

AF:

0.524

EpiControl

AF:

0.533

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (3)

Diabetes mellitus, transient neonatal, 2 (2)

Hyperinsulinemic hypoglycemia, familial, 1 (2)

Diabetes mellitus, permanent neonatal 3 (1)

Hereditary hyperinsulinism (1)

Hyperinsulinemia (1)

Leucine-induced hypoglycemia (1)

Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.61

(source)

DANN

Benign

0.59

PhyloP100

-2.6

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over