rs1340859533

chr11-17397276-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000352.6(ABCC8):c.3905C>T(p.Ala1302Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,872 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: 0.0000014 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.99

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_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 283) in uniprot entity ABCC8_HUMAN there are 108 pathogenic changes around while only 12 benign (90%) in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.3905C>T	p.Ala1302Val	missense_variant	32/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.3905C>T	p.Ala1302Val	missense_variant	32/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460872 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726804

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 (rs1340859533) in MODY yet. -

Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Apr 14, 2017

- -

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 (rs1340859533) in neonatal diabetes yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
Polyphen		0.77	.;.;P;.;.;.;.;.
Vest4		0.91, 0.91
MutPred		0.54		.;.;Gain of MoRF binding (P = 0.1834);.;.;.;Gain of MoRF binding (P = 0.1834);.;
MVP		0.95
MPC		1.0
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.72
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1340859533; hg19: chr11-17418823;