11-17408375-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000352.6(ABCC8):c.2820+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 1,609,408 control chromosomes in the GnomAD database, including 304,157 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 0.62 (29149 hom., cov: 30)
  • Exomes 𝑓: 0.61 (275008 hom.)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.585

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-17408375-T-C is Benign according to our data. Variant chr11-17408375-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157694.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=8}. Variant chr11-17408375-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.2820+17A>G		intron_variant		ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.2820+17A>G		intron_variant		1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93620 AN: 151644 Hom.: 29135 Cov.: 30

Gnomad AFR AF: 0.615

Gnomad AMI AF: 0.725

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.692

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.635

GnomAD3 exomes AF: 0.616 AC: 153601 AN: 249280 Hom.: 48161 AF XY: 0.606 AC XY: 81781 AN XY: 134964

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.701

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.746

Gnomad SAS exome AF: 0.464

Gnomad FIN exome AF: 0.522

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.612 AC: 891559 AN: 1457646 Hom.: 275008 Cov.: 35 AF XY: 0.608 AC XY: 440756 AN XY: 725276

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.696

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.715

Gnomad4 SAS exome AF: 0.468

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.617 AC: 93692 AN: 151762 Hom.: 29149 Cov.: 30 AF XY: 0.609 AC XY: 45198 AN XY: 74170

Gnomad4 AFR AF: 0.615

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.665

Gnomad4 EAS AF: 0.723

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.624

Gnomad4 OTH AF: 0.634

Alfa AF: 0.631 Hom.: 52168

Bravo AF: 0.634

Asia WGS AF: 0.563 AC: 1956 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs2106865) in MODY yet. -

Transitory neonatal diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs2106865) in neonatal diabetes yet. -

Leucine-induced hypoglycemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Diabetes mellitus, transient neonatal, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Hyperinsulinemic hypoglycemia, familial, 1 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	4.5
Dann	Benign	0.76

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: rs2106865; hg19: chr11-17429922; COSMIC: COSV56847309; COSMIC: COSV56847309;