rs200670692

Positions:

chr11-17476715-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000352.6(ABCC8):c.62T>A(p.Val21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,609,238 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 (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.04

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a topological_domain Extracellular (size 33) in uniprot entity ABCC8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000352.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

PP5

Variant 11-17476715-A-T is Pathogenic according to our data. Variant chr11-17476715-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495835.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.62T>A	p.Val21Asp	missense_variant	1/39	ENST00000389817.8	NP_000343.2
LOC124902641	XR_007062609.1 linkuse as main transcript	n.65A>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.62T>A	p.Val21Asp	missense_variant	1/39	1	NM_000352.6	ENSP00000374467	P4	Q09428-1
	ENST00000662030.1 linkuse as main transcript	n.121A>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000582

AC:

AN:

240646

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

131126

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1457486

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

724920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151752

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74112

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000378

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000991

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 11, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Aug 16, 2023	The p.Val21Asp variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 19475716, 20685672, 23345197, 23275527), and has been identified 0.011% (14/122860) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200670692). 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: 495835) and has been interpreted as pathogenic/likely pathogenic by Invitae, Natera Inc., Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Counsyl and Fulgent Genetics. Of the many affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, and 1 was a homozygote, which increases the likelihood that the p.Val21Asp variant is pathogenic (Variation ID: 633026; PMID: 16357843, 19475716, 20685672, 23345197, 23275527). In vitro functional studies provide some evidence that the p.Val21Asp variant may slightly impact protein function (PMID: 27573238). However, these types of assays may not accurately represent biological function. 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, PP3, PS3_supporting (Richards 2015). -

Familial hyperinsulinism

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 23, 2017

Variant summary: The ABCC8 c.62T>A (p.Val21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. Although the variant is located outside of any known functional domain of the ATP-regulated potassium channels, 5/5 in silico tools predict a deleterious outcome for this variant. This variant was found in 12/88122 control chromosomes at a frequency of 0.0001362, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). Furthermore, this variant was identified homozygously or in compound heterozygosity in multiple diazoxide-unresponsive comprehensively genotyped neonatal patients with biochemically and histologically confirmed diagnosed diffuse CHI which is inherited in an autosomal recessive manner. Although no in-vitro functional studies supporting a loss of function of the ATP regulated potassium channels have been reported, the available patient characteristics provide in-vivo evidence demonstrating a damaging effect of this variant on channel function. Taken together, the ascertained evidence has been weighted to classify this variant as Pathogenic. -

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 04, 2024

- -

Hereditary hyperinsulinism

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 30, 2021

- -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 15, 2021

- -

ABCC8-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

This variant has been previously reported as homozygous and compound heterozygous change in patients with congenital hyperinsulinemic hypoglycemia (PMID: 23345197, 19475716). The c.62T>A (p.Val21Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/271858) and is absent in the homozygous state, thus is presumed to be rare. The c.62T>A (p.Val21Asp) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.62T>A (p.Val21Asp) variant is classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 21 of the ABCC8 protein (p.Val21Asp). This variant is present in population databases (rs200670692, gnomAD 0.01%). This missense change has been observed in individuals with recessive congenital hyperinsulinism (PMID: 19475716, 20685672, 23345197). ClinVar contains an entry for this variant (Variation ID: 495835). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 27573238). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

.;.;T;.;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.87

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Uncertain

2.3

.;M;M;M;.;.;.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-3.0

.;.;D;D;.;.;.;.;.

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

.;.;D;D;.;.;.;.;.

Sift4G

Uncertain

0.0020

.;.;D;D;.;.;.;.;D

Polyphen

1.0

.;.;D;.;.;.;.;.;.

Vest4

0.87, 0.88, 0.99

MVP

0.96

MPC

1.1

ClinPred

0.75

GERP RS

3.0

Varity_R

0.92

gMVP

0.95

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