rs137852673

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000389817.8(ABCC8):c.4135C>T(p.Arg1379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1379H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ABCC8
ENST00000389817.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.57

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000389817.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17395914-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-17395915-G-A is Pathogenic according to our data. Variant chr11-17395915-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9105.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.4135C>T	p.Arg1379Cys	missense_variant	34/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4135C>T	p.Arg1379Cys	missense_variant	34/39	1	NM_000352.6	ENSP00000374467	P4	Q09428-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000497

AC:

AN:

201102

Hom.:

AF XY:

0.00000930

AC XY:

AN XY:

107540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000329

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1432938

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000241

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000834

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

ABCC8-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2024

The ABCC8 c.4135C>T variant is predicted to result in the amino acid substitution p.Arg1379Cys. This variant has been reported to be pathogenic for transient neonatal diabetes (TNDM) in an autosomal dominant manner (Babenko et al. 2006. PubMed ID: 16885549). Of note, different substitutions at the same codon have also been reported to cause neonatal diabetes (p.Arg1379Ser at Bennett et al. 2015. PubMed ID: 25555642; p.Arg1379His reported as R1380H at Bowman et al. 2012. PubMed ID: 21989597; p.Arg1379Leu reported as R1380L at Rafiq et al. 2008. PubMed ID: 18025408).This variant is reported in 0.0033% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Monogenic diabetes

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg1379Cys (sometimes called p.Arg1380Cys) variant in ABCC8 has been reported in 7 individuals with Monogenic Diabetes, segregated with disease in 4 affected relatives from 1 family (PMID: 16885549, 17446535, 25306193), and has been identified in 0.003286% (1/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Trio analysis showed this variant to be de novo with unconfirmed maternity and paternity in one individual reported in the literature (PMID: 17446535). This variant has also been reported pathogenic in ClinVar (Variation ID: 9105). In vitro functional studies provide some evidence that the p.Arg1379Cys variant may slightly increase the rate of ATP hydrolysis (PMID: 18025464). 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. Three additional variants with a different amino acid change at the same position, (p.Arg1379His, p.Arg1379Leu and p.Arg1379Ser), have been reported in association with disease in ClinVar or have been curated likely pathogenic or as variants of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615, 35614). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM6, PM5_supporting, PS3_supporting, PM2_Supporting, PP3, PS4_Supporting, PP1 (Richards 2015). -

Diabetes mellitus, transient neonatal, 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1379 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 17446535), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18025464). 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: 9105). This variant is also known as R1380C. This missense change has been observed in individuals with autosomal dominant ABCC8-related early onset diabetes (PMID: 16885549, 17446535, 27681997). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1379 of the ABCC8 protein (p.Arg1379Cys). -

Permanent neonatal diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

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

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

.;.;H;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96, 0.97

MutPred

0.97

.;.;Loss of disorder (P = 0.0172);.;.;.;Loss of disorder (P = 0.0172);.;

MVP

0.94

MPC

2.1

ClinPred

1.0

GERP RS

5.1

Varity_R

0.97

gMVP

0.89

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