rs2301703

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_000352.6(ABCC8):c.579+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,592,216 control chromosomes in the GnomAD database, including 129,616 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 0.47 ( 18440 hom., cov: 32)

Exomes 𝑓: 0.39 ( 111176 hom. )

Consequence

ABCC8
NM_000352.6 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 0.634

Publications

13 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=-0.78).

BP6

Variant 11-17463424-G-A is Benign according to our data. Variant chr11-17463424-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157707.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.694 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.579+14C>T	intron	N/A	NP_000343.2	Q09428-1
ABCC8	NM_001351295.2		c.579+14C>T	intron	N/A	NP_001338224.1	A0A2R8Y4V0
ABCC8	NM_001287174.3		c.579+14C>T	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.579+14C>T	intron	N/A	ENSP00000374467.4	Q09428-1
ABCC8	ENST00000644772.1		c.579+14C>T	intron	N/A	ENSP00000494321.1	A0A2R8Y4V0
ABCC8	ENST00000302539.9	TSL:5	c.579+14C>T	intron	N/A	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes

AF:

0.470

AC:

71455

AN:

151990

Hom.:

18395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.701

Gnomad AMI

AF:

0.391

Gnomad AMR

AF:

0.429

Gnomad ASJ

AF:

0.477

Gnomad EAS

AF:

0.401

Gnomad SAS

AF:

0.295

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.538

Gnomad NFE

AF:

0.385

Gnomad OTH

AF:

0.475

GnomAD2 exomes

AF:

0.389

AC:

85736

AN:

220200

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.708

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.475

Gnomad EAS exome

AF:

0.382

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.381

Gnomad OTH exome

AF:

0.400

GnomAD4 exome

AF:

0.387

AC:

557883

AN:

1440108

Hom.:

111176

Cov.:

AF XY:

0.384

AC XY:

274462

AN XY:

714258

show subpopulations

African (AFR)

AF:

0.715

AC:

23722

AN:

33162

American (AMR)

AF:

0.409

AC:

17065

AN:

41764

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

12037

AN:

25634

East Asian (EAS)

AF:

0.389

AC:

15168

AN:

39040

South Asian (SAS)

AF:

0.291

AC:

24104

AN:

82804

European-Finnish (FIN)

AF:

0.299

AC:

15545

AN:

51918

Middle Eastern (MID)

AF:

0.466

AC:

2647

AN:

5676

European-Non Finnish (NFE)

AF:

0.384

AC:

422867

AN:

1100450

Other (OTH)

AF:

0.414

AC:

24728

AN:

59660

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

16721

33443

50164

66886

83607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13358

26716

40074

53432

66790

<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:

0.470

AC:

71544

AN:

152108

Hom.:

18440

Cov.:

AF XY:

0.464

AC XY:

34481

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.701

AC:

29098

AN:

41500

American (AMR)

AF:

0.429

AC:

6560

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.477

AC:

1656

AN:

3470

East Asian (EAS)

AF:

0.400

AC:

2059

AN:

5146

South Asian (SAS)

AF:

0.296

AC:

1425

AN:

4822

European-Finnish (FIN)

AF:

0.291

AC:

3085

AN:

10600

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.385

AC:

26157

AN:

67958

Other (OTH)

AF:

0.471

AC:

992

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1819

3639

5458

7278

9097

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

620

1240

1860

2480

3100

<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:

0.429

Hom.:

6918

Bravo

AF:

0.493

Asia WGS

AF:

0.356

AC:

1240

AN:

3478

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, transient neonatal, 2 (2)

Hyperinsulinemic hypoglycemia, familial, 1 (2)

Diabetes mellitus, permanent neonatal 3 (1)

Leucine-induced hypoglycemia (1)

Permanent neonatal diabetes mellitus (1)

Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.3

(source)

DANN

Benign

0.71

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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