Genetic Variant NM_000352.6:c.2277C>T (chr11-17415318-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000352.6(ABCC8):c.2277C>T(p.Thr759Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,610,186 control chromosomes in the GnomAD database, including 1,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T759T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.028 ( 94 hom., cov: 33)

Exomes 𝑓: 0.044 ( 1661 hom. )

Consequence

ABCC8
NM_000352.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.480

Publications

28 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 -21 ACMG points.

BP4

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

BP6

Variant 11-17415318-G-A is Benign according to our data. Variant chr11-17415318-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.48 with no splicing effect.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0519 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	UniProt
ABCC8	NM_000352.6	MANE Select	c.2277C>T	p.Thr759Thr	synonymous	Exon 18 of 39	NP_000343.2	Q09428-1
ABCC8	NM_001351295.2		c.2343C>T	p.Thr781Thr	synonymous	Exon 18 of 39	NP_001338224.1	A0A2R8Y4V0
ABCC8	NM_001287174.3		c.2280C>T	p.Thr760Thr	synonymous	Exon 18 of 39	NP_001274103.1	Q09428-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.2277C>T	p.Thr759Thr	synonymous	Exon 18 of 39	ENSP00000374467.4	Q09428-1
ABCC8	ENST00000644772.1		c.2343C>T	p.Thr781Thr	synonymous	Exon 18 of 39	ENSP00000494321.1	A0A2R8Y4V0
ABCC8	ENST00000302539.9	TSL:5	c.2280C>T	p.Thr760Thr	synonymous	Exon 18 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes

AF:

0.0281

AC:

4273

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00881

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0217

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00849

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0461

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0272

AC:

6624

AN:

243136

AF XY:

0.0273

show subpopulations

Gnomad AFR exome

AF:

0.00754

Gnomad AMR exome

AF:

0.0132

Gnomad ASJ exome

AF:

0.00995

Gnomad EAS exome

AF:

0.000166

Gnomad FIN exome

AF:

0.0297

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0301

GnomAD4 exome

AF:

0.0437

AC:

63700

AN:

1457940

Hom.:

1661

Cov.:

AF XY:

0.0423

AC XY:

30687

AN XY:

724626

show subpopulations

African (AFR)

AF:

0.00699

AC:

234

AN:

33456

American (AMR)

AF:

0.0127

AC:

563

AN:

44220

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

262

AN:

25980

East Asian (EAS)

AF:

0.000101

AC:

AN:

39640

South Asian (SAS)

AF:

0.00952

AC:

806

AN:

84702

European-Finnish (FIN)

AF:

0.0318

AC:

1692

AN:

53162

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0523

AC:

58048

AN:

1110756

Other (OTH)

AF:

0.0343

AC:

2067

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3763

7525

11288

15050

18813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2198

4396

6594

8792

10990

<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:

0.0281

AC:

4271

AN:

152246

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1990

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00878

AC:

365

AN:

41564

American (AMR)

AF:

0.0216

AC:

331

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.000388

AC:

AN:

5158

South Asian (SAS)

AF:

0.00850

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0277

AC:

294

AN:

10604

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0461

AC:

3134

AN:

68016

Other (OTH)

AF:

0.0180

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0413

Hom.:

557

Bravo

AF:

0.0267

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Diabetes mellitus, transient neonatal, 2 (1)

Hereditary hyperinsulinism (1)

Hyperinsulinemic hypoglycemia, familial, 1 (1)

Inborn genetic diseases (1)

Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.20

(source)

DANN

Benign

0.42

PhyloP100

-0.48

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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