11-17404524-C-T

Position:

• chr11-17404524-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000352.6(ABCC8):​c.3545G>A​(p.Arg1182Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1182W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.89

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 70) in uniprot entity ABCC8_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr11-17404525-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 11-17404524-C-T is Pathogenic according to our data. Variant chr11-17404524-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 35611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.3545G>A	p.Arg1182Gln	missense_variant	28/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.3545G>A	p.Arg1182Gln	missense_variant	28/39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727198

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 13, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1182 of the ABCC8 protein (p.Arg1182Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant neonatal diabetes mellitus (PMID: 16885549, 17446535, 22749773, 24622368). This variant is also known as Arg1183Gln. ClinVar contains an entry for this variant (Variation ID: 35611). 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. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 22451668). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Neonatal diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 25, 2024

- -

Diabetes mellitus, transient neonatal, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 17, 2019

DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.3545G>A, in exon 28 that results in an amino acid change, p.Arg1182Gln. This sequence change has been previously described in patients with transient neonatal diabetes, in both the de novo (PMID: 17389331) and familial state (PMIDs: 16885549, 22749773). It was identified in a father of one patient who presented with type 2 diabetes occurring later in life which was treated with diet alone (PMID: 16885549). Another missense variant affecting the same amino acid residue, p.Arg1182Trp, has also been described in patients with neonatal diabetes presenting with severe hyperglycemia (Flanagan et al., 2007). This sequence change has not been described in the population databases such as ExAC and gnomAD (dbSNP rs193922400). The p.Arg1182Gln change affects a highly conserved amino acid residue located in a functional domain of the ABCC8 protein that is known to be functional. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	.;.;D;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	.;.;N;N;.;.;.;.
REVEL	Pathogenic	0.77
Sift	Benign	0.049	.;.;D;D;.;.;.;.
Sift4G	Benign	0.065	.;.;T;T;.;.;.;.
Polyphen		0.098	.;.;B;.;.;.;.;.
Vest4		0.96
MutPred		0.91		.;.;Gain of methylation at K1179 (P = 0.0471);.;.;.;Gain of methylation at K1179 (P = 0.0471);.;
MVP		0.91
MPC		0.90
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.60		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs193922400; hg19: chr11-17426071;