chr11-17395659-G-A

Position:

• chr11-17395659-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000352.6(ABCC8):​c.4258C>T​(p.Arg1420Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000994 in 1,408,732 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 11-17395659-G-A is Pathogenic according to our data. Variant chr11-17395659-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9095.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	c.4258C>T	p.Arg1420Cys	missense_variant	35/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.4258C>T	p.Arg1420Cys	missense_variant	35/39	1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000994 AC: 14 AN: 1408732 Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 7 AN XY: 695626

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: 0.00

Gnomad4 NFE exome AF: 0.0000120

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2019	The ABCC8 c.4258C>T (p.Arg1420Cys) missense variant, also referred to as c.4261C>T, (p.Arg1421Cys), has been reported in at least six studies in which it is found in a total of seven individuals with congenital hyperinsulinism, including in a homozygous state in three individuals (two of whom are siblings), in a compound heterozygous state in one individual, in a heterozygous state in one individual and in two individuals with unknown zygosity (Verkarre et al. 1998; de Lonlay-Debeney et al. 1999; Tanizawa et al. 2000; Bellanné-Chantelot et al. 2010; Snider et al. 2013; Kappor et al. 2013). The variant was absent from 480 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. The Arg1420 residue is highly conserved. Matsuo et al. (2000) analyzed the functional effect of the p.Arg1420Cys variant and showed it lowers affinity for ATP and ADP binding and leads to enhanced insulin secretion. Tanizawa et al. (2000) transiently expressed the variant protein in COS-7 cells and showed inhibition of channel formation and function compared to wild type. Based on the collective evidence, the p.Arg1420Cys variant is classified as pathogenic for congenital hyperinsulinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 29, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1420 of the ABCC8 protein (p.Arg1420Cys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 10615958, 10993895, 26246406). 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. ClinVar contains an entry for this variant (Variation ID: 9095). This variant is also known as p.Arg1421Cys. This missense change has been observed in individuals with clinical features of dyslipidemia and/or familial hyperinsulinemia (PMID: 9769320, 10615958, 17378627, 32041611). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Published functional studies demonstrate a damaging effect and show that this variant leads to channel function impairment (Tanizawa et al., 2000; Matsuo et al., 2000; Baier et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.4261C>T, R1421C; This variant is associated with the following publications: (PMID: 32041611, 36208030, 20685672, 23275527, 31479591, 17378627, 28587604, 10202168, 26246406, 9769320, 10615958, 23345197, 10993895) -

Type 2 diabetes mellitus Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 08, 2023

- -

Hereditary hyperinsulinism Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 23, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.3	.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.2	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;D;.;.;.;.
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.94, 0.94
MutPred		0.86		.;.;Loss of methylation at R1420 (P = 0.0376);.;.;.;Loss of methylation at R1420 (P = 0.0376);.;
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs28938469; hg19: chr11-17417206; COSMIC: COSV56847151; COSMIC: COSV56847151;