rs797045213

Positions:

• chr11-17463454-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000352.6(ABCC8):​c.563A>G​(p.Asn188Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,258 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N188N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a transmembrane_region Helical; Name=5 (size 26) in uniprot entity ABCC8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-17463454-T-C is Pathogenic according to our data. Variant chr11-17463454-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.563A>G	p.Asn188Ser	missense_variant	4/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.563A>G	p.Asn188Ser	missense_variant	4/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453258 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 16, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 23, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2019	Variant summary: ABCC8 c.563A>G (p.Asn188Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 235752 control chromosomes (gnomAD). c.563A>G has been reported in the literature in multiple individuals affected with Congenital or Familial Hyperinsulinism (Shyng_1998, Nestorowicz_1998, Christesen_2001, Del Roio Liberatore_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Shyng_2008, found the variant to form channels that were indistinguishable from the wild-type in terms of regulation of the channel by nucleotides and diazoxide. However, the authors do indicate the variant could be playing a role in transcription, translation, trafficking or stability of protein, where were not assessed. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 18, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. ClinVar contains an entry for this variant (Variation ID: 210082). This missense change has been observed in individual(s) with autosomal recessive diffuse or focal hyperinsulinism (PMID: 15562009, 16429405, 24434300, 24686051, 28442472). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 188 of the ABCC8 protein (p.Asn188Ser). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 16, 2017	- -

Type 2 diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

Hereditary hyperinsulinism Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 04, 2021

- -

Diabetes mellitus, permanent neonatal 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

May 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
Polyphen		0.62	.;.;P;.;.;.;.;.
Vest4		0.94, 0.94
MutPred		0.80		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.91
MPC		0.26
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.24
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045213; hg19: chr11-17485001;