rs797045208

Variant names:

• chr11-17474937-A-C
• rs797045208
• NM_000352.6:c.239T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP5

The NM_000352.6(ABCC8):​c.239T>G​(p.Met80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M80T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.27
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinemic hypoglycemia, familial, 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial hyperinsulinism

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• diabetes mellitus

  Inheritance: SD Classification: DEFINITIVE Submitted by: Ambry Genetics
• monogenic diabetes

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypoglycemia, leucine-induced

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• diabetes mellitus, transient neonatal, 2

  Inheritance: Unknown, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to SUR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000352.6
• PP5: Variant 11-17474937-A-C is Pathogenic according to our data. Variant chr11-17474937-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210073.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.239T>G	p.Met80Arg	missense_variant	Exon 2 of 39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.239T>G	p.Met80Arg	missense_variant	Exon 2 of 39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251434 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461864 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000994 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1 Uncertain:1

Aug 16, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Met80Arg variant in ABCC8 has been previously reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 17378627, 28442472), and has been seen in 0.0009% (1/113722) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs797045208). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 210073) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met80Arg variant is pathogenic (PMID: 17378627). In vitro functional studies provide some evidence that the p.Met80Arg variant may slightly impact protein function (PMID: 31821855). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Met80Arg variant is uncertain. ACMG/AMP Criteria applied: PM3, PS3_supporting, PM2_supporting (Richards 2015). -

Jun 11, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 Pathogenic:1

Apr 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	.;.;D;.;.;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.0	.;N;N;N;.;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	.;.;N;N;.;.;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0060	.;.;D;D;.;.;.;.
Polyphen		0.010	.;.;B;.;.;.;.;.
Vest4		0.64, 0.63
MutPred		0.75		Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);Gain of catalytic residue at M80 (P = 0.0032);
MVP		0.85
MPC		0.39
ClinPred		0.63	D
GERP RS		5.2
Varity_R		0.79
gMVP		0.92
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797045208; hg19: chr11-17496484;