rs1801261

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000352.6(ABCC8):c.2277C>T(p.Thr759=) 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:10

Conservation

PhyloP100: -0.480

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 157689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17415318-G-A is described in Lovd as [Benign]. Variant chr11-17415318-G-A is described in Lovd as [Likely_benign].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.2277C>T	p.Thr759=	synonymous_variant	18/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.2277C>T	p.Thr759=	synonymous_variant	18/39	1	NM_000352.6	P4	Q09428-1

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

GnomAD3 exomes

AF:

0.0272

AC:

6624

AN:

243136

Hom.:

142

AF XY:

0.0273

AC XY:

3577

AN XY:

130962

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 SAS exome

AF:

0.00885

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

Gnomad4 AFR exome

AF:

0.00699

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00952

Gnomad4 FIN exome

AF:

0.0318

Gnomad4 NFE exome

AF:

0.0523

Gnomad4 OTH exome

AF:

0.0343

GnomAD4 genome

AF:

0.0281

AC:

4271

AN:

152246

Hom.:

Cov.:

AF XY:

0.0267

AC XY:

1990

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00878

Gnomad4 AMR

AF:

0.0216

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.0277

Gnomad4 NFE

AF:

0.0461

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0422

Hom.:

276

Bravo

AF:

0.0267

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2019	This variant is associated with the following publications: (PMID: 24768178, 22902787, 9075812, 25955821, 24959012, 22704848, 18758683, 18599530, 15842514, 15111507, 11246895, 31118371, 11289470) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 14, 2018	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Diabetes mellitus, transient neonatal, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Permanent neonatal diabetes mellitus

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

Cadd

Benign

0.20

Dann

Benign

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over