rs142272833

chr11-17393742-C-Achr11-17393742-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000352.6(ABCC8):c.4563G>T(p.Lys1521Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 0.409

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017162055).
• BP6: Variant 11-17393742-C-A is Benign according to our data. Variant chr11-17393742-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434043.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Benign=1, Likely_benign=1}. Variant chr11-17393742-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4563G>T	p.Lys1521Asn	missense_variant	38/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4563G>T	p.Lys1521Asn	missense_variant	38/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes AF: 0.00115 AC: 175 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251288 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135802

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461814 Hom.: 0 Cov.: 34 AF XY: 0.000111 AC XY: 81 AN XY: 727202

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.000179

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: 0.00000899

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.00115 AC: 175 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74510

Gnomad4 AFR AF: 0.00418

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000195 Hom.: 1

Bravo AF: 0.00146

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Previously reported in two children with obesity (Foucan et al., 2018); This variant is associated with the following publications: (PMID: 29216354) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 24, 2015

- -

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs142272833) in MODY yet. -

Transitory neonatal diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs142272833) in neonatal diabetes yet. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 29, 2018

ACMG criteria: [PP3 (4 predictors), BP4 (6 predictors), REVEL = 0.392, conflicting evidence so not using], BS2 (15 cases and 14 controls in type2diabetesgenetics.org, ABCC8 causes AD and AR d/o), BS3 (PMID: 18346985, functional assays showed no different from wild type) = Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D;D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
Polyphen		0.45	.;.;B;.;.;.;.;.
Vest4		0.91, 0.93
MutPred		0.81		.;.;Loss of methylation at K1521 (P = 0.0127);.;.;.;Loss of methylation at K1521 (P = 0.0127);.;
MVP		0.81
MPC		0.85
ClinPred		0.054	T
GERP RS		3.2
Varity_R		0.25
gMVP		0.91

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: rs142272833; hg19: chr11-17415289;