11-17427095-C-T

Position:

chr11-17427095-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000352.6(ABCC8):c.2176G>A(p.Ala726Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00081 in 1,613,880 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 2 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 2.11

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:

ABCC8 (HGNC:):

ABCC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a domain ABC transporter 1 (size 250) in uniprot entity ABCC8_HUMAN there are 14 pathogenic changes around while only 5 benign (74%) in NM_000352.6

BP4

Computational evidence support a benign effect (MetaRNN=0.029074907).

BP6

Variant 11-17427095-C-T is Benign according to our data. Variant chr11-17427095-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434050.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, Benign=1}. Variant chr11-17427095-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.2176G>A	p.Ala726Thr	missense_variant	16/39	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.2176G>A	p.Ala726Thr	missense_variant	16/39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000717

AC:

109

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

251224

Hom.:

AF XY:

0.000457

AC XY:

AN XY:

135766

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000522

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000765

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000820

AC:

1198

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

576

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.00102

Gnomad4 OTH exome

AF:

0.000497

GnomAD4 genome

AF:

0.000716

AC:

109

AN:

152206

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000818

Hom.:

Bravo

AF:

0.000650

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.00125

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 19, 2021	NM_000352.3(ABCC8):c.2176G>A(A726T) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. A726T has been observed in cases with relevant disease (PMID: 23345197, 24401662, 26758964). Functional assessments of this variant are not available in the literature. A726T has been observed in population frequency databases (gnomAD: NFE 0.08%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.2176G>A(A726T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 31, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2022	Variant summary: ABCC8 c.2176G>A (p.Ala726Thr) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain 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 0.00045 in 251224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.00045 vs 0.0034), allowing no conclusion about variant significance. c.2176G>A has been reported in the literature in individuals affected with Familial Hyperinsulinism or pulmonary arterial hypertension. These reports do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign/likely benign n=3, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2021	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2024	Identified in additional patients with congenital hyperinsulinism, however, a second ABCC8 variant was not identified (PMID: 21378087, 23345197, 24401662); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32934261, 24401662, 23345197, 32027066, 21378087, 26758964) -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1833104:Permanent neonatal diabetes mellitus;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary hyperinsulinism

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 21, 2020

- -

Permanent neonatal diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 31, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Diabetes mellitus, transient neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 31, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Uncertain

0.56

.;.;D;.;.;.;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.74

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

M_CAP

Benign

0.046

MetaRNN

Benign

0.029

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

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

.;L;L;L;.;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.19

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

REVEL

Benign

0.15

Sift

Benign

0.38

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

Sift4G

Benign

0.25

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

Polyphen

0.0

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

Vest4

0.34, 0.34

MVP

0.82

MPC

0.25

ClinPred

0.017

GERP RS

2.9

Varity_R

0.11

gMVP

0.41

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