rs1800853

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.797

Variant links:

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]

ABCC8 links:

ABCC8 (HGNC:):

ABCC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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: {Uncertain_significance=1, Benign=10}. 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 GnomAd4 at 35 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.4120-19C>T		intron_variant		ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4120-19C>T		intron_variant		1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0140

AC:

2128

AN:

152234

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0168

AC XY:

1481

AN XY:

87988

show subpopulations

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.:

AF XY:

0.00727

AC XY:

5062

AN XY:

695900

show subpopulations

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.:

Cov.:

AF XY:

0.0143

AC XY:

1065

AN XY:

74500

show subpopulations

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.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.0550

AC:

191

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	This variant is associated with the following publications: (PMID: 16429405, 33410562, 27884173) -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ABCC8: BS1, BS2 -

not specified

Benign:3

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. -
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	-	- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over