rs145136257

Positions:

• chr11-17453232-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000352.6(ABCC8):​c.1063G>A​(p.Ala355Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000699 in 1,613,994 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A355A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (1 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:4
• Conservation: PhyloP100: 4.00

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15245563).
• BP6: Variant 11-17453232-C-T is Benign according to our data. Variant chr11-17453232-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210066.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.1063G>A	p.Ala355Thr	missense_variant	7/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.1063G>A	p.Ala355Thr	missense_variant	7/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.000579 AC: 88 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00115

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000461 AC: 116 AN: 251468 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135912

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000941

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000711 AC: 1040 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000670 AC XY: 487 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000889

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000579 AC: 88 AN: 152114 Hom.: 1 Cov.: 32 AF XY: 0.000485 AC XY: 36 AN XY: 74288

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00115

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000749 Hom.: 0

Bravo AF: 0.000521

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:7

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 30, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in the heterozygous state in a patient with permanent neonatal diabetes and a patient with congenital hyperinsulinism (Russo et al., 2011; Kapoor et el., 2013), and observed in the heterozygous state with a second variant in cis in a patient with congenital hyperinsulinism (Ismail et al., 2011); however, also observed in the heterozyous state in many unaffected, unrelated individuals referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 31604004, 20943779, 23345197, 21544516) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the ABCC8 protein (p.Ala355Thr). This variant is present in population databases (rs145136257, gnomAD 0.09%). This missense change has been observed in individual(s) with congenital hyperinsulinism or persistent neonatal diabetes mellitus (PMID: 20943779, 21544516, 24401662, 27908292, 28442472). ClinVar contains an entry for this variant (Variation ID: 210066). 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 not expected to disrupt ABCC8 protein function. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2023	Variant summary: ABCC8 c.1063G>A (p.Ala355Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00046 vs 0.0034), allowing no conclusion about variant significance. c.1063G>A has been reported in the literature in individuals affected with Congenital Hyperinsulinism without strong evidence of causality (e.g. Hussain_2005, Snider_2013, Kapoor_2013, Mohnike_2014, Li_2017, Ismail_2011). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. Co-occurrences with another pathogenic variant in cis has been reported (ABCC8 c.4477C>T, p.Arg1493Trp, Ismail_2011), providing supporting evidence for a benign role. 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: 16186397, 23275527, 23345197, 24401662, 28442472, 36407475, 20943779). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. 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. -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.1063G>A (p.A355T) alteration is located in exon 7 (coding exon 7) of the ABCC8 gene. This alteration results from a G to A substitution at nucleotide position 1063, causing the alanine (A) at amino acid position 355 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary hyperinsulinism Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 19, 2021

- -

Diabetes mellitus, transient neonatal, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Permanent neonatal diabetes mellitus Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
Polyphen		0.31	.;.;B;.;.;.;.;.
Vest4		0.66, 0.66
MVP		0.92
MPC		0.27
ClinPred		0.034	T
GERP RS		5.8
Varity_R		0.52
gMVP		0.92

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

Other links and lift over

dbSNP: rs145136257; hg19: chr11-17474779;