rs796891223

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000352.6(ABCC8):ā€‹c.4591A>Gā€‹(p.Thr1531Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 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 Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1531P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

11
7
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.45
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000352.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ABCC8NM_000352.6 linkuse as main transcriptc.4591A>G p.Thr1531Ala missense_variant 38/39 ENST00000389817.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ABCC8ENST00000389817.8 linkuse as main transcriptc.4591A>G p.Thr1531Ala missense_variant 38/391 NM_000352.6 P4Q09428-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461858
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727222
show subpopulations
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 28, 2021DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4591A>G, in exon 38 that results in an amino acid change, p.Thr1531Ala. This sequence change has not been described in population database including gnomAD. The p.Thr1531Ala change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Thr1531Ala substitution. This sequence change has previously been reported in the compound heterozygous state with another ABCC8 variant in an individual with congenital hyperinsulinism (PMID: 19475716). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Thr1531Ala change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
.;.;D;.;.;.;.;.
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Pathogenic
3.0
.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-4.3
.;.;D;D;.;.;.;.
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0020
.;.;D;D;.;.;.;.
Sift4G
Uncertain
0.0020
.;.;D;D;.;.;.;.
Polyphen
0.95
.;.;P;.;.;.;.;.
Vest4
0.98
MutPred
0.98
.;.;Loss of stability (P = 0.2417);.;.;.;Loss of stability (P = 0.2417);.;
MVP
0.94
MPC
1.4
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.79
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-17415261; API