rs72559722

Positions:

chr11-17412716-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000352.6(ABCC8):c.2506C>T(p.Arg836*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,611,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 1.86

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-17412716-G-A is Pathogenic according to our data. Variant chr11-17412716-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188915.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.2506C>T	p.Arg836*	stop_gained	21/39	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.2506C>T	p.Arg836*	stop_gained	21/39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000608

AC:

AN:

246774

Hom.:

AF XY:

0.0000450

AC XY:

AN XY:

133252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000206

AC:

AN:

1459556

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725730

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000247

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74262

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2021	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2506C>T, which results in the creation of a premature stop codon at amino acid position 836, p.Arg836*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ABCC8 protein with potentially abnormal function. This pathogenic sequence change has previously been described in a patients with both diffuse and focal ABCC8-related hyperinsulinism (PMIDs: 15579781,26379717, 25765446). Functional studies have also demonstrated that this sequence change may impact protein function (PMID: 15579781). -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 16, 2023	The p.Arg836Ter variant in ABCC8 has been reported in at least 11 individuals with congenital hyperinsulinism (PMID: 30386300, 26740944, 17378627, 26379717, 28701683, 23345197, 25765446, 23301914, 21422196), and has been identified in 0.03% (12/35140) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559722). 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 (VariationID: 188915) as pathogenic or likely pathogenic by 11 submitters. Of the 11 affected individuals, 1 of those was a homozygote and 5 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Arg836Ter variant is pathogenic (Variation ID: 188864, 939498; PMID: 26740944, 26379717, 28701683, 23345197, 25765446, 21422196). In vitro functional studies provide some evidence that the p.Arg836Ter variant may slightly impact protein function (PMID: 15579781). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 836, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 09, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2019	Variant summary: ABCC8 c.2506C>T (p.Arg836X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.1e-05 in 246774 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (6.1e-05 vs 0.0034). c.2506C>T has been reported in the literature, in compound heterozygous and homozygous state, in individuals affected with Congenital Hyperinsulinism (Tornovsky_2004, Yorifuji_2011). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant severely impacts trafficking of the channel to the plasma membrane (it did not reach the plasma membrane at all), which in turn causes a substantial defect in channel activity (Tornovsky_2004). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Mar 29, 2019	This nonsense variant is predicted to result in loss of normal protein function. The variant has been previously reported in ClinVar as likely pathogenic (Variation ID: 188915). This variant has been described in the heterozygous, compound heterozygous, and homozygous state in diffuse and focal congenital hyperinsulinism (PMID: 23067144, 23345197, 23301914, 26379717, 29644095). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.00006 (17/272624) and thus is presumed to be rare. The c.2506C>T (p.Arg836Ter) variant is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2506C>T (p.Arg836Ter) variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	May 21, 2024	This variant is found to be a potent High impact, deleterious variant with a CADD score of 40 and sufficient recent scientific evidence for both gene and variant correlation with the condition. Hence, this variant is reclassified as Likely pathogenic. -

not provided

Pathogenic:4

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	GeneDx	Nov 09, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as c.2509C>T p.(R837*); This variant is associated with the following publications: (PMID: 17378627, 20943781, 23067144, 26379717, 29644095, 24332968, 10923633, 25555642, 25525159, 23301914, 2563966, 23345197, 25765446, 10204114, 15579781, 21422196, 21968108, 25639667, 26740944, 28701683, 31019026) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change creates a premature translational stop signal (p.Arg836*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (rs72559722, gnomAD 0.04%). This premature translational stop signal has been observed in individuals with congenital hyperinsulinism (PMID: 23067144, 23301914, 23345197, 26379717, 29644095). This variant is also known as c.2509C>T, p.Arg837X. ClinVar contains an entry for this variant (Variation ID: 188915). For these reasons, this variant has been classified as Pathogenic. -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1833104:Permanent neonatal diabetes mellitus;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Neonatal diabetes mellitus

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

May 21, 2024

This variant is found to be a potent High impact, deleterious variant with a CADD score of 40 and sufficient scientific evidence of gene-disease correlation Hence, this variant is reclassified as Likely pathogenic. -

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

Hereditary hyperinsulinism

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.88

Vest4

0.98

GERP RS

3.8

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