rs185040406

Positions:

chr11-17460675-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000352.6(ABCC8):c.824G>A(p.Arg275Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,607,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R275W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 2 hom. )

Consequence

ABCC8
NM_000352.6 missense, splice_region

Scores

Splicing: ADA: 0.0003166

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 0.0850

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 -7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 116) in uniprot entity ABCC8_HUMAN there are 26 pathogenic changes around while only 3 benign (90%) in NM_000352.6

BP4

Computational evidence support a benign effect (MetaRNN=0.018305808).

BP6

Variant 11-17460675-C-T is Benign according to our data. Variant chr11-17460675-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225291.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=6, Benign=2}.

BS2

High Homozygotes in GnomAdExome4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant, splice_region_variant	6/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.824G>A	p.Arg275Gln	missense_variant, splice_region_variant	6/39	1	NM_000352.6	P4	Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152226

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:

0.00251

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000238

AC:

AN:

244080

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

132884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00229

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1455362

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

724290

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00297

Gnomad4 SAS exome

AF:

0.000360

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000105

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 12, 2019

- -

Permanent neonatal diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Type 2 diabetes mellitus

Benign:1

Likely benign, criteria provided, single submitter

reference population

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Mar 18, 2016

- -

Hereditary hyperinsulinism

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 07, 2020

- -

Diabetes mellitus, transient neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

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

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.064

MetaRNN

Benign

0.017

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

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.55

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

MutationTaster

Benign

0.78

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.94

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

REVEL

Uncertain

0.57

Sift

Benign

0.076

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

Sift4G

Benign

0.21

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

Polyphen

0.0020

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

Vest4

0.20, 0.20

MVP

0.80

MPC

0.30

ClinPred

0.033

GERP RS

2.6

Varity_R

0.094

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.034

SpliceAI score (max)

0.91

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.91

Position offset: -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