11-17463184-C-T

Variant names:

• chr11-17463184-C-T
• rs4148609
• NM_000352.6:c.579+254G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000352.6(ABCC8):​c.579+254G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,022 control chromosomes in the GnomAD database, including 8,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (8524 hom., cov: 32)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0530
• Publications: 10 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-17463184-C-T is Benign according to our data. Variant chr11-17463184-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276933.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.579+254G>A		intron_variant	Intron 4 of 38	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.579+254G>A		intron_variant	Intron 4 of 38	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50511 AN: 151904 Hom.: 8523 Cov.: 32

Gnomad AFR AF: 0.321

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.373

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.332 AC: 50524 AN: 152022 Hom.: 8524 Cov.: 32 AF XY: 0.328 AC XY: 24333 AN XY: 74296

African (AFR) AF: 0.321 AC: 13314 AN: 41464

American (AMR) AF: 0.366 AC: 5593 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1381 AN: 3468

East Asian (EAS) AF: 0.393 AC: 2026 AN: 5150

South Asian (SAS) AF: 0.214 AC: 1029 AN: 4798

European-Finnish (FIN) AF: 0.247 AC: 2611 AN: 10582

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23313 AN: 67962

Other (OTH) AF: 0.370 AC: 779 AN: 2108

Alfa AF: 0.349 Hom.: 15462

Bravo AF: 0.344

Asia WGS AF: 0.277 AC: 962 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.59
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism (auto)

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: rs4148609; hg19: chr11-17484731;