rs757110

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000352.6(ABCC8):c.4105G>T(p.Ala1369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,778 control chromosomes in the GnomAD database, including 341,651 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 40061 hom., cov: 34)

Exomes 𝑓: 0.64 ( 301590 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.0710

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 -18 ACMG points.

PM1

In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6

BP4

Computational evidence support a benign effect (MetaRNN=1.2142411E-6).

BP6

Variant 11-17396930-C-A is Benign according to our data. Variant chr11-17396930-C-A is described in ClinVar as [Benign]. Clinvar id is 157699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17396930-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.4105G>T	p.Ala1369Ser	missense_variant	33/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4105G>T	p.Ala1369Ser	missense_variant	33/39	1	NM_000352.6	ENSP00000374467	P4	Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.712

AC:

108208

AN:

151974

Hom.:

40001

Cov.:

show subpopulations

Gnomad AFR

AF:

0.933

Gnomad AMI

AF:

0.480

Gnomad AMR

AF:

0.670

Gnomad ASJ

AF:

0.624

Gnomad EAS

AF:

0.629

Gnomad SAS

AF:

0.610

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.684

Gnomad NFE

AF:

0.637

Gnomad OTH

AF:

0.688

GnomAD3 exomes

AF:

0.636

AC:

159547

AN:

251040

Hom.:

51719

AF XY:

0.630

AC XY:

85500

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.939

Gnomad AMR exome

AF:

0.618

Gnomad ASJ exome

AF:

0.611

Gnomad EAS exome

AF:

0.621

Gnomad SAS exome

AF:

0.616

Gnomad FIN exome

AF:

0.519

Gnomad NFE exome

AF:

0.630

Gnomad OTH exome

AF:

0.628

GnomAD4 exome

AF:

0.640

AC:

935098

AN:

1461686

Hom.:

301590

Cov.:

AF XY:

0.637

AC XY:

463383

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.947

Gnomad4 AMR exome

AF:

0.624

Gnomad4 ASJ exome

AF:

0.616

Gnomad4 EAS exome

AF:

0.614

Gnomad4 SAS exome

AF:

0.618

Gnomad4 FIN exome

AF:

0.522

Gnomad4 NFE exome

AF:

0.639

Gnomad4 OTH exome

AF:

0.651

GnomAD4 genome

AF:

0.712

AC:

108332

AN:

152092

Hom.:

40061

Cov.:

AF XY:

0.706

AC XY:

52448

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.934

Gnomad4 AMR

AF:

0.670

Gnomad4 ASJ

AF:

0.624

Gnomad4 EAS

AF:

0.630

Gnomad4 SAS

AF:

0.609

Gnomad4 FIN

AF:

0.530

Gnomad4 NFE

AF:

0.637

Gnomad4 OTH

AF:

0.688

Alfa

AF:

0.642

Hom.:

78390

Bravo

AF:

0.728

TwinsUK

AF:

0.648

AC:

2404

ALSPAC

AF:

0.633

AC:

2440

ESP6500AA

AF:

0.932

AC:

4101

ESP6500EA

AF:

0.639

AC:

5490

ExAC

AF:

0.643

AC:

78021

Asia WGS

AF:

0.651

AC:

2263

AN:

3478

EpiCase

AF:

0.636

EpiControl

AF:

0.637

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	This variant is associated with the following publications: (PMID: 28411266, 25955821, 26551672, 27398621, 11117432, 22209866, 17823772, 25143473, 22187380, 19587354) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in this gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation have a better response to sulfonylureas. It doesn't cause any sensitivity toward mild hypoglycemia, an adverse effect of Sulfonylurea treatment. -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Leucine-induced hypoglycemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Hyperinsulinism, Dominant/Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Diabetes mellitus, transient neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Diabetes mellitus, permanent neonatal 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Permanent neonatal diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Transient Neonatal Diabetes, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

2.4

DANN

Benign

0.16

DEOGEN2

Uncertain

0.48

.;.;T;.;.;.;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.14

T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0000012

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

.;.;N;.;.;.;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.98

.;.;N;N;.;.;.;.

REVEL

Uncertain

0.51

Sift

Benign

0.41

.;.;T;T;.;.;.;.

Sift4G

Benign

0.43

.;.;T;T;.;.;.;.

Polyphen

0.0

.;.;B;.;.;.;.;.

Vest4

0.016, 0.014

MPC

0.64

ClinPred

0.00031

GERP RS

2.4

Varity_R

0.11

gMVP

0.36

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

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