11-17395872-C-T

Position:

chr11-17395872-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_000352.6(ABCC8):c.4178G>A(p.Arg1393His) variant causes a missense change. The variant allele was found at a frequency of 0.0000365 in 1,587,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1393C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:3

Conservation

PhyloP100: 6.16

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 Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000352.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17395873-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2418967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-17395872-C-T is Pathogenic according to our data. Variant chr11-17395872-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 446776.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.4178G>A	p.Arg1393His	missense_variant	34/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4178G>A	p.Arg1393His	missense_variant	34/39	1	NM_000352.6	P4	Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000385

AC:

AN:

207710

Hom.:

AF XY:

0.00000901

AC XY:

AN XY:

110950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000326

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000624

Gnomad SAS exome

AF:

0.0000774

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

AN:

1434990

Hom.:

Cov.:

AF XY:

0.0000295

AC XY:

AN XY:

710692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000903

Gnomad4 AMR exome

AF:

0.0000242

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.0000244

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.0000401

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 24, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1393 of the ABCC8 protein (p.Arg1393His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital hyperinsulinism (PMID: 9618169). This variant is also known as R1394H. ClinVar contains an entry for this variant (Variation ID: 446776). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840, 11457841, 17575084). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2022	Reported in a patient with familial hyperinsulinism who also harbors an additional variant in the ABCC8 gene (Nestorowicz et al., 1998); Also known as p.R1394H (c.4181G>A); Published functional studies using transfected cells were not consistent in their results regarding the potential effect of this variant on channel function and protein trafficking (Shyng et al., 1998; Partridge et al., 2001; Yan et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9648840, 17575084, 32041611, 11457841, 17956278, 24399968, 14707124, 9618169, 23226049) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 06, 2018	- -

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 16, 2023	The p.Arg1393His variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 9648840, 9618169, 32041611) and has been identified in 0.008% (2/25832) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769279368). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 446776) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago), Natera Inc., and Athena Diagnostics Inc., and as a variant of uncertain significance by Myriad Women's Health Inc. and Counsyl. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1393His variant is pathogenic (Variation ID: 9088; PMID: 9648840). In vitro functional studies provide some evidence that the p.Arg1393His variant may impact protein function (PMID: 9648840, 11457841). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting, PS3_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 10, 2021	NM_000352.3(ABCC8):c.4178G>A(R1393H) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. R1393H has been observed in cases with relevant disease (PMID: 9618169). Functional assessments of this variant are available in the literature (PMID: 9648840, 11457841). R1393H has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.4178G>A(R1393H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Type 2 diabetes mellitus

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 20, 2023

- -

Hereditary hyperinsulinism

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Maturity onset diabetes mellitus in young

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Diabetes Institute, Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

Polyphen

1.0

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

Vest4

0.99

MutPred

0.97

.;.;Loss of stability (P = 0.0487);.;.;.;Loss of stability (P = 0.0487);.;

MVP

0.95

MPC

2.0

ClinPred

0.82

GERP RS

4.2

Varity_R

0.66

gMVP

0.91

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