rs1800853

chr11-17395949-G-Achr11-17395949-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000352.6(ABCC8):c.4120-19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 1,561,592 control chromosomes in the GnomAD database, including 192 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 0.014 (35 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (157 hom.)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.797

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=-0.8).
• BP6: Variant 11-17395949-G-A is Benign according to our data. Variant chr11-17395949-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35612.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Uncertain_significance=1}. Variant chr11-17395949-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0141 (2143/152352) while in subpopulation AMR AF= 0.0292 (447/15312). AF 95% confidence interval is 0.027. There are 35 homozygotes in gnomad4. There are 1065 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4120-19C>T		intron_variant		ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4120-19C>T		intron_variant		1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 152234 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0240

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00298

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0177 AC: 2943 AN: 165810 Hom.: 66 AF XY: 0.0168 AC XY: 1481 AN XY: 87988

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.0509

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.0256

Gnomad SAS exome AF: 0.0270

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.00687 AC: 9684 AN: 1409240 Hom.: 157 Cov.: 31 AF XY: 0.00727 AC XY: 5062 AN XY: 695900

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.0483

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.0255

Gnomad4 FIN exome AF: 0.000325

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.0141 AC: 2143 AN: 152352 Hom.: 35 Cov.: 33 AF XY: 0.0143 AC XY: 1065 AN XY: 74500

Gnomad4 AFR AF: 0.0274

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.0260

Gnomad4 SAS AF: 0.0236

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.00800 Hom.: 3

Bravo AF: 0.0173

Asia WGS AF: 0.0550 AC: 191 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	ABCC8: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	This variant is associated with the following publications: (PMID: 16429405, 33410562, 27884173) -

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2016	Variant summary: The ABCC8 c.4120-19C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 604/26462 control chromosomes (11 homozygotes) at a frequency of 0.0228252, which greatly exceeds the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (2.1e-8), suggesting this variant is a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together and based on the prevalence in general population this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperinsulinemia 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 response to sulfonylureas. Although rs1800853 is prevalent in hyperinsulinemic hypoglycemia in infancy, sufficient evidence is not seen to demonstrate the 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, 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	-0.80
Cadd	Benign	6.2
Dann	Benign	0.71

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: rs1800853; hg19: chr11-17417496;