NM_000352.6:c.291-62G>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000352.6(ABCC8):c.291-62G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,610,324 control chromosomes in the GnomAD database, including 2,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 1248 hom., cov: 32)

Exomes 𝑓: 0.011 ( 1203 hom. )

Consequence

ABCC8
NM_000352.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.317

Publications

4 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 -20 ACMG points.

BP4

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

BP6

Variant 11-17470284-C-A is Benign according to our data. Variant chr11-17470284-C-A is described in ClinVar as Benign. ClinVar VariationId is 1251559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.291-62G>T		intron_variant	Intron 2 of 38	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.291-62G>T		intron_variant	Intron 2 of 38	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0738

AC:

11227

AN:

152106

Hom.:

1240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.0573

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0605

Gnomad NFE

AF:

0.00366

Gnomad OTH

AF:

0.0565

GnomAD4 exome

AF:

0.0111

AC:

16232

AN:

1458100

Hom.:

1203

Cov.:

AF XY:

0.0105

AC XY:

7580

AN XY:

725018

show subpopulations

African (AFR)

AF:

0.246

AC:

8235

AN:

33418

American (AMR)

AF:

0.0191

AC:

849

AN:

44418

Ashkenazi Jewish (ASJ)

AF:

0.0572

AC:

1492

AN:

26098

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39672

South Asian (SAS)

AF:

0.00915

AC:

783

AN:

85590

European-Finnish (FIN)

AF:

0.000664

AC:

AN:

52704

Middle Eastern (MID)

AF:

0.0713

AC:

352

AN:

4934

European-Non Finnish (NFE)

AF:

0.00265

AC:

2948

AN:

1111032

Other (OTH)

AF:

0.0255

AC:

1536

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

740

1480

2221

2961

3701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

310

620

930

1240

1550

<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:

0.0740

AC:

11262

AN:

152224

Hom.:

1248

Cov.:

AF XY:

0.0709

AC XY:

5278

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.242

AC:

10049

AN:

41498

American (AMR)

AF:

0.0388

AC:

594

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

199

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00366

AC:

249

AN:

68024

Other (OTH)

AF:

0.0559

AC:

118

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

467

935

1402

1870

2337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0308

Hom.:

500

Bravo

AF:

0.0854

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 17, 2018

GeneDx

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

-0.83

CADD

Benign

8.2

(source)

DANN

Benign

0.63

PhyloP100

0.32

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