chr11-17428382-C-T

Position:

• chr11-17428382-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_000352.6(ABCC8):​c.1947G>A​(p.Lys649=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,742 control chromosomes in the GnomAD database, including 22,375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (2216 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20159 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 1.86

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-17428382-C-T is Benign according to our data. Variant chr11-17428382-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157686.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.1947G>A	p.Lys649=	synonymous_variant	14/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.1947G>A	p.Lys649=	synonymous_variant	14/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25218 AN: 152044 Hom.: 2214 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.174 AC: 43615 AN: 250856 Hom.: 4271 AF XY: 0.178 AC XY: 24148 AN XY: 135654

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.292

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.160 AC: 233646 AN: 1461580 Hom.: 20159 Cov.: 33 AF XY: 0.163 AC XY: 118674 AN XY: 727072

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.198

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.166 AC: 25250 AN: 152162 Hom.: 2216 Cov.: 33 AF XY: 0.171 AC XY: 12737 AN XY: 74382

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.191

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.155

Alfa AF: 0.152 Hom.: 1176

Bravo AF: 0.159

Asia WGS AF: 0.292 AC: 1013 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely 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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:3

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -

Diabetes mellitus, transient neonatal, 2 Benign:2

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	This variant is associated with the following publications: (PMID: 14551916) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are generally associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. However, though the prevalence of rs1799858 in congenital hyperinsulinism of Infancy is seen, there is no sufficient evidence to show association of this variant with neonatal diabetes or MODY. -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Leucine-induced hypoglycemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Diabetes mellitus, permanent neonatal 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Permanent neonatal diabetes mellitus Benign:1

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.4
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799858; hg19: chr11-17449929; COSMIC: COSV56849597; COSMIC: COSV56849597;