chr11-17406616-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000352.6(ABCC8):c.3329+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,611,936 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 12 hom., cov: 32)

Exomes 𝑓: 0.018 ( 281 hom. )

Consequence

ABCC8
NM_000352.6 splice_region, intron

Scores

Splicing: ADA: 0.00002013

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.518

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-17406616-G-A is Benign according to our data. Variant chr11-17406616-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17406616-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1929/152264) while in subpopulation NFE AF= 0.0186 (1263/68018). AF 95% confidence interval is 0.0177. There are 12 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.3329+6C>T		splice_region_variant, intron_variant	Intron 26 of 38	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.3329+6C>T		splice_region_variant, intron_variant	Intron 26 of 38	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1931

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00862

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00933

Gnomad FIN

AF:

0.0128

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.0114

AC:

2845

AN:

249098

Hom.:

AF XY:

0.0114

AC XY:

1529

AN XY:

134630

show subpopulations

Gnomad AFR exome

AF:

0.00998

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00560

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00715

Gnomad FIN exome

AF:

0.0114

Gnomad NFE exome

AF:

0.0176

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.0178

AC:

26049

AN:

1459672

Hom.:

281

Cov.:

AF XY:

0.0172

AC XY:

12459

AN XY:

725766

show subpopulations

Gnomad4 AFR exome

AF:

0.00754

Gnomad4 AMR exome

AF:

0.00406

Gnomad4 ASJ exome

AF:

0.00556

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.00787

Gnomad4 FIN exome

AF:

0.0112

Gnomad4 NFE exome

AF:

0.0210

Gnomad4 OTH exome

AF:

0.0135

GnomAD4 genome

AF:

0.0127

AC:

1929

AN:

152264

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

852

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00859

Gnomad4 AMR

AF:

0.00542

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00892

Gnomad4 FIN

AF:

0.0128

Gnomad4 NFE

AF:

0.0186

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0167

Hom.:

Bravo

AF:

0.0123

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0163

EpiControl

AF:

0.0168

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ABCC8: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2025	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 23652837) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2018	Variant summary: ABCC8 c.3329+6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.012 in 274898 control chromosomes in the gnomAD database, including 26 homozygotes. The observed variant frequency is approximately 557705.035 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Neonatal Diabetes Mellitus phenotype (2.1e-08), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Diabetes mellitus, transient neonatal, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

Permanent neonatal diabetes mellitus

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

Transitory neonatal diabetes mellitus

Benign:1

Benign, 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 respond to sulfonylureas. However, no sufficient evidence is found to ascertain the role of rs113873225 variant in Diabetes Mellitus yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.41

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000020

dbscSNV1_RF

Benign

0.0020

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