rs1554905695

chr11-17396939-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000352.6(ABCC8):c.4096G>A(p.Ala1366Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1366D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4096G>A	p.Ala1366Thr	missense_variant	33/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4096G>A	p.Ala1366Thr	missense_variant	33/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Benign	0.065
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;.;T;T;T;T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
Polyphen		0.15	.;.;B;.;.;.;.;.
Vest4		0.90, 0.90
MutPred		0.57		.;.;Loss of sheet (P = 0.0817);.;.;.;Loss of sheet (P = 0.0817);.;
MVP		0.89
MPC		0.78
ClinPred		0.66	D
GERP RS		4.8
Varity_R		0.68
gMVP		0.86

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

Other links and lift over

dbSNP: rs1554905695; hg19: chr11-17418486;