chr11-17393023-C-T

Position:

chr11-17393023-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_000352.6(ABCC8):c.4714G>A(p.Val1572Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0575 in 1,614,124 control chromosomes in the GnomAD database, including 3,148 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.050 ( 226 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2922 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:16

Conservation

PhyloP100: 0.486

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 Benign. Variant got -11 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0015296042).

BP6

Variant 11-17393023-C-T is Benign according to our data. Variant chr11-17393023-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157705.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=12}.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.4714G>A	p.Val1572Ile	missense_variant	39/39	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.4714G>A	p.Val1572Ile	missense_variant	39/39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0506

AC:

7697

AN:

152226

Hom.:

225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0299

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0475

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.0370

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0637

Gnomad OTH

AF:

0.0626

GnomAD3 exomes

AF:

0.0549

AC:

13812

AN:

251374

Hom.:

522

AF XY:

0.0585

AC XY:

7947

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0289

Gnomad AMR exome

AF:

0.0294

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.0681

Gnomad FIN exome

AF:

0.0404

Gnomad NFE exome

AF:

0.0662

Gnomad OTH exome

AF:

0.0709

GnomAD4 exome

AF:

0.0582

AC:

85132

AN:

1461780

Hom.:

2922

Cov.:

AF XY:

0.0594

AC XY:

43161

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0305

Gnomad4 AMR exome

AF:

0.0323

Gnomad4 ASJ exome

AF:

0.145

Gnomad4 EAS exome

AF:

0.00471

Gnomad4 SAS exome

AF:

0.0682

Gnomad4 FIN exome

AF:

0.0393

Gnomad4 NFE exome

AF:

0.0597

Gnomad4 OTH exome

AF:

0.0621

GnomAD4 genome

AF:

0.0505

AC:

7691

AN:

152344

Hom.:

226

Cov.:

AF XY:

0.0488

AC XY:

3637

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0298

Gnomad4 AMR

AF:

0.0475

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.00173

Gnomad4 SAS

AF:

0.0559

Gnomad4 FIN

AF:

0.0370

Gnomad4 NFE

AF:

0.0637

Gnomad4 OTH

AF:

0.0614

Alfa

AF:

0.0632

Hom.:

861

Bravo

AF:

0.0501

TwinsUK

AF:

0.0512

AC:

190

ALSPAC

AF:

0.0542

AC:

209

ESP6500AA

AF:

0.0350

AC:

154

ESP6500EA

AF:

0.0659

AC:

566

ExAC

AF:

0.0561

AC:

6817

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0714

EpiControl

AF:

0.0724

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hyperinsulinemic hypoglycemia, familial, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Diabetes mellitus, transient neonatal, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Neonatal hypoglycemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Mutations in the ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation have a better response to sulfonylureas. However, the significance of rs8192690 in neonatal Diabetes Mellitus is uncertain. -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Leucine-induced hypoglycemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Hyperinsulinism, Dominant/Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Diabetes mellitus, permanent neonatal 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Transient Neonatal Diabetes, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Permanent neonatal diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.33

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

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.85

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

MetaRNN

Benign

0.0015

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.10

.;.;N;.;.;.;.;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.090

.;.;N;N;.;.;.;.

REVEL

Benign

0.17

Sift

Benign

0.46

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

Sift4G

Benign

0.93

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

Polyphen

0.0050

.;.;B;.;.;.;.;.

Vest4

0.031, 0.030

MPC

0.57

ClinPred

0.00077

GERP RS

1.3

Varity_R

0.021

gMVP

0.69

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