NM_000352.6:c.1384A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000352.6(ABCC8):c.1384A>G(p.Ile462Val) variant causes a missense change. The variant allele was found at a frequency of 0.00169 in 1,614,100 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:5

Conservation

PhyloP100: 4.24

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022486657).

BP6

Variant 11-17443261-T-C is Benign according to our data. Variant chr11-17443261-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210068.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=5}. Variant chr11-17443261-T-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.1384A>G	p.Ile462Val	missense_variant	Exon 9 of 39	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.1384A>G	p.Ile462Val	missense_variant	Exon 9 of 39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000894

AC:

136

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00166

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000875

AC:

220

AN:

251358

Hom.:

AF XY:

0.000869

AC XY:

118

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00180

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00177

AC:

2590

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1275

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00226

Gnomad4 OTH exome

AF:

0.000911

GnomAD4 genome

AF:

0.000894

AC:

136

AN:

152208

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00166

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.000914

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.000840

AC:

102

EpiCase

AF:

0.00109

EpiControl

AF:

0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jan 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCC8 c.1384A>G (p.Ile462Val) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 251358 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00088 vs 0.0034), allowing no conclusion about variant significance. c.1384A>G has been reported in the literature in individuals affected with Congenital Hyperinsulinism without strong evidence of causality (e.g. Sandal_2009, Snider_2013). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19475716, 23275527, 27913849). ClinVar contains an entry for this variant (Variation ID: 210068). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 10, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 462 of the ABCC8 protein (p.Ile462Val). This variant is present in population databases (rs117874766, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with congenital hyperinsulinism (PMID: 19475716). ClinVar contains an entry for this variant (Variation ID: 210068). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ABCC8 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 07, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Type 2 diabetes mellitus

Uncertain:1

Jan 24, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hereditary hyperinsulinism

Uncertain:1

Apr 03, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

ABCC8-related disorder

Uncertain:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCC8 c.1384A>G variant is predicted to result in the amino acid substitution p.Ile462Val. This variant has been reported in a Norwegian patient with CHI (Sandal et al. 2009. PubMed ID: 19475716). The patient reported by Sandal et al. inherited the c.1384A>G (p.Ile462Val) variant and a splicing variant from the mother while the paternal allele is a nonsense pathogenic change. Sandal et al. suggested that the major deleterious effect on the maternal allele is from the splicing variant and the c.1384A>G (p.Ile462Val) variant may contribute less, if at all. Therefore, its clinical significance has not been established with sufficient evidence This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect this change is more likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Type 2 diabetes mellitus;C2931832:Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:1

May 08, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An ABCC8 c.1384A>G (p.Ile462Val) missense variant was identified in a heterozygous state. This variant has been identified in the literature in 2 affected siblings who each inherited three ABCC8 variants, the p.Ile462Val variant and a splicing variant on the maternal allele and a nonsense variant on the paternal allele. Since both individuals had other variants expected to cause disease, the p.Ile462Val variant was interpreted as non-causal (Sandal T et al., PMID: 19475716). It has also been reported in an individual with congenital hyperinsulinism but was interpreted as non-causal (Snider KE et al., PMID: 23275527). This variant is observed on 257/282,726 alleles in the general population (gnomAD v.2.1.1). Computational predictors suggest that this variant does not impact ABCC8 function. This variant has been reported in the ClinVar database as a germline variant of uncertain significance by 5 submitters and a likely benign variant by 3 submitters (ClinVar ID: 210068). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Inborn genetic diseases

Benign:1

Feb 28, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Diabetes mellitus, transient neonatal, 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Permanent neonatal diabetes mellitus

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

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

M_CAP

Benign

0.037

MetaRNN

Benign

0.022

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

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.16

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

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.19

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

REVEL

Benign

0.23

Sift

Benign

0.48

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

Sift4G

Benign

0.58

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

Polyphen

0.0050

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

Vest4

0.39, 0.39

MVP

0.76

MPC

0.22

ClinPred

0.0072

GERP RS

4.9

Varity_R

0.12

gMVP

0.53

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

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