chr11-17476643-G-A

Position:

• chr11-17476643-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000352.6(ABCC8):​c.134C>T​(p.Pro45Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,882 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.71

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.134C>T	p.Pro45Leu	missense_variant	1/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.134C>T	p.Pro45Leu	missense_variant	1/39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459882 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726278

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: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diabetes mellitus, permanent neonatal 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the ABCC8 protein (p.Pro45Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with permanent neonatal diabetes mellitus (PMID: 17668386, 18025408, 25972930). ClinVar contains an entry for this variant (Variation ID: 9110). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	.;M;M;M;.;.;.;.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.2	.;.;N;N;.;.;.;.;.
REVEL	Pathogenic	0.82
Sift	Benign	0.13	.;.;T;T;.;.;.;.;.
Sift4G	Benign	0.20	.;.;T;T;.;.;.;.;D
Polyphen		0.59	.;.;P;.;.;.;.;.;.
Vest4		0.81, 0.81, 0.98
MutPred		0.81		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.94
MPC		0.93
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.52
gMVP		0.87

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: rs267606623; hg19: chr11-17498190;