11-17397055-C-T

Position:

chr11-17397055-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_000352.6(ABCC8):c.3989-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000185 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 intron

Scores

Splicing: ADA: 0.001703

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 0.305

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-17397055-C-T is Pathogenic according to our data. Variant chr11-17397055-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.3989-9G>A		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.3989-9G>A		intron_variant		1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251406

Hom.:

AF XY:

0.000316

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00605

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000185

AC:

271

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000198

AC XY:

144

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00681

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000177

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000542

Hom.:

Bravo

AF:

0.000166

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change falls in intron 32 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. This variant is present in population databases (rs151344623, gnomAD 0.6%). This variant has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 7716548, 27754802). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8923011, 21716120). This variant is also known as 3992‚Äì9g‚Üía. ClinVar contains an entry for this variant (Variation ID: 9088). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 7716548). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2022	Published functional studies suggest that c.3989-9G>A activates a preexisting cryptic 3splice site within exon 33, resulting in out-of-frame product (Saint-Martin et al., 2021); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25972930, 7716548, 8923011, 20672374, 27754802, 21716120, 25306193, 31980526, 31589614, 33726816, 33410562) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 23, 2013	- -

Hyperinsulinemic hypoglycemia, familial, 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 26, 2019	NM_000352.3(ABCC8):c.3989-9G>A is classified as pathogenic in the context of ABCC8-related familial hyperinsulinism. Sources cited for classification include the following: PMID 10447255, 7716548, 23345197, 11999683, 11272143, 24401662, 15579781, 21851374, 16860127 and 8923011. Classification of NM_000352.3(ABCC8):c.3989-9G>A is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 16, 2023	The c.3989-9G>A variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 25306193, 25972930, 16429405, 16860127, 27175728, 17378627, 11272143, 27754802), and has been identified In 0.6% (62/10366) or Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs151344623). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 9088) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 3 were compound heterozygotes that carried a reported pathogenic variant in trans, and 4 of those were homozygotes, which increases the likelihood that the c.3989-9G>A variant is pathogenic (Variation ID: 188864, 9096; PMID: 16429405, 16860127, 17378627). RNAseq analysis performed on affected tissue shows a deletion of the first 20 nucleotides of exon 33 (PMID: 33410562). This variant is located in the 3’ splice region. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PS3, PP3 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.029%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.70). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25306193) and co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 27754802, 7716548). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000009088). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial hyperinsulinism

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2017	Variant summary: The ABCC8 variant, c.3989-9G>A (alternatively also known as 3992-9G>A) involves the alteration of a non-conserved intronic nucleotide in intron 32. Mutation taster predicts a disease-causing outcome for this variant. While Human Splicing Finder predicts this variant to form a cryptic splice acceptor site, other four splice prediction tools predict no significant impact on normal splicing. Functional study shows that this variant leads to aberrant splicing, resulting in a 7-bp addition, a 20-bp deletion, or 30-bp deletion of exon 32 that encodes NBF-2 (nucleotide binding fold 2) of the protein (Thomas_1995). This variant was found in 373/164074 control chromosomes including ExAC at a frequency of 0.0022734, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). This variant is a known common pathogenic variant causing congenital hyperinsulinism (CH). In Ashkenazi population, c.39899G>A and p.F1387del are the two most common CH-associated ABCC8 mutations (Nestorowicz_1998, Glaser_2011). Carrier rate of this mutation in Ashkenazi general population is 1:60 (Glaser_2011). In GeneReviews, proportion of familial CH attributed to these two mutations is estimated to be nearly 45%. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008867.1(NM_001287174.1):c.3992-9G>A in the ABCC8 gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been observed to segregate with familial hyperinsulinism and affect RNA splicing (PMID: 7716548). In addition, Gutgold et al. reported a male with recurrent hypoglycemia episodes and revealed a homozygosity for c.3992-9G>A (PMID: 27754802). Experimental studies have shown that this intronic change alters ABCC8 splicing (PMID: 7716548). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PS3; PM3; PP4. -

Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 07, 2022

- -

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.3989-9G>A intronic alteration results from a G to A substitution 9 nucleotides before coding exon 33 of the ABCC8 gene. Based on the available evidence, the ABCC8 c.3989-9G>A alteration is classified as pathogenic for familial hyperinsulinemic hypoglycemia, but is unlikely to be causative of autosomal dominant ABCC8-related diabetes mellitus. This alteration has been reported in the homozygous and compound heterozygous states and in the heterozygous state on the paternal allele in multiple individuals with congenital hyperinsulinemic hypoglycemia (Del Roio Liberatore, 2015; Glaser, 2011; Gutgold, 2017; Nestorowicz, 1996; Thomas, 1995). This is also a common founder mutation in the Ashkenazi Jewish population (Glaser, 2011; Nestorowicz, 1996). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Hereditary hyperinsulinism

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

ABCC8-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The ABCC8 c.3989-9G>A variant is predicted to interfere with splicing. This variant has been previously reported to be pathogenic for persistent hyperinsulinemic hypoglycemia due to defective splicing (Thomas et al. 1995. PubMed ID: 7716548; Nestorowicz et al. 1996. PubMed ID: 8923011). In Family 4 of the Thomas et al. study, this variant occurred in the homozygous state in two affected siblings and was heterozygous in both unaffected parents. In the Nestorowicz et al. study, out of the 23 probands who had this variant, 11 were homozygotes and 12 were heterozygotes. This variant is reported in 0.60% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. In summary, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.2

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0017

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.25

Position offset: -2

DS_AL_spliceai

0.70

Position offset: -9

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