rs8192690

chr11-17393023-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_000352.6(ABCC8):c.4714G>A(p.Val1572Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,614,124 control chromosomes in the GnomAD database, including 3,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.050 (226 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2922 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 0.486

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 Benign. Variant got -11 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 106 pathogenic changes around while only 11 benign (91%) in NM_000352.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015296042).
• BP6: Variant 11-17393023-C-T is Benign according to our data. Variant chr11-17393023-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157705.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=12, Likely_benign=2}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4714G>A	p.Val1572Ile	missense_variant	39/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4714G>A	p.Val1572Ile	missense_variant	39/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.0506 AC: 7697 AN: 152226 Hom.: 225 Cov.: 33

Gnomad AFR AF: 0.0299

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0475

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0637

Gnomad OTH AF: 0.0626

GnomAD3 exomes AF: 0.0549 AC: 13812 AN: 251374 Hom.: 522 AF XY: 0.0585 AC XY: 7947 AN XY: 135870

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.0294

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0681

Gnomad FIN exome AF: 0.0404

Gnomad NFE exome AF: 0.0662

Gnomad OTH exome AF: 0.0709

GnomAD4 exome AF: 0.0582 AC: 85132 AN: 1461780 Hom.: 2922 Cov.: 32 AF XY: 0.0594 AC XY: 43161 AN XY: 727190

Gnomad4 AFR exome AF: 0.0305

Gnomad4 AMR exome AF: 0.0323

Gnomad4 ASJ exome AF: 0.145

Gnomad4 EAS exome AF: 0.00471

Gnomad4 SAS exome AF: 0.0682

Gnomad4 FIN exome AF: 0.0393

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0621

GnomAD4 genome AF: 0.0505 AC: 7691 AN: 152344 Hom.: 226 Cov.: 33 AF XY: 0.0488 AC XY: 3637 AN XY: 74500

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.0475

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0559

Gnomad4 FIN AF: 0.0370

Gnomad4 NFE AF: 0.0637

Gnomad4 OTH AF: 0.0614

Alfa AF: 0.0632 Hom.: 861

Bravo AF: 0.0501

TwinsUK AF: 0.0512 AC: 190

ALSPAC AF: 0.0542 AC: 209

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.0659 AC: 566

ExAC AF: 0.0561 AC: 6817

Asia WGS AF: 0.0250 AC: 88 AN: 3478

EpiCase AF: 0.0714

EpiControl AF: 0.0724

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:16

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Diabetes mellitus, transient neonatal, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Neonatal hypoglycemia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in the ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation have a better response to sulfonylureas. However, the significance of rs8192690 in neonatal Diabetes Mellitus is uncertain. -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Leucine-induced hypoglycemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Hyperinsulinism, Dominant/Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Diabetes mellitus, permanent neonatal 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Transient Neonatal Diabetes, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Permanent neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	10
Dann	Benign	0.86
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.85	D;.;D;D;D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.30	T
Polyphen		0.0050	.;.;B;.;.;.;.;.
Vest4		0.031, 0.030
MPC		0.57
ClinPred		0.00077	T
GERP RS		1.3
Varity_R		0.021
gMVP		0.69

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: rs8192690; hg19: chr11-17414570; COSMIC: COSV56855126; COSMIC: COSV56855126;