11-17460675-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

3
16
Splicing: ADA: 0.0003166
2

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]

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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
ABCC8NM_000352.6 linkuse as main transcriptc.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
ABCC8ENST00000389817.8 linkuse as main transcriptc.824G>A p.Arg275Gln missense_variant, splice_region_variant 6/391 NM_000352.6 P4Q09428-1

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152226
Hom.:
0
Cov.:
33
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:
58
AN:
244080
Hom.:
1
AF XY:
0.000218
AC XY:
29
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.:
2
Cov.:
32
AF XY:
0.000127
AC XY:
92
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:
16
AN:
152344
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
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.:
0
Bravo
AF:
0.000121
ExAC
AF:
0.000231
AC:
28
Asia WGS
AF:
0.00115
AC:
4
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 submitterclinical testingRevvity Omics, RevvityDec 22, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 19, 2016- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 05, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 12, 2019- -
Permanent neonatal diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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 submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Hereditary hyperinsulinism Benign:1
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Oct 07, 2020- -
Diabetes mellitus, transient neonatal, 2 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.40
.;.;T;.;.;.;.;.
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.38
N
LIST_S2
Benign
0.78
T;.;T;T;T;T;T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.017
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
0.55
.;N;N;N;.;.;.;.
MutationTaster
Benign
0.78
N;N
PrimateAI
Benign
0.27
T
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
T
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.

Other links and lift over

dbSNP: rs185040406; hg19: chr11-17482222; COSMIC: COSV56845572; COSMIC: COSV56845572; API