11-17476848-C-A

Variant names:

• chr11-17476848-C-A
• rs541244107
• ENST00000683136.1:c.-72G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000683136.1(ABCC8):​c.-72G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,108,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: ABCC8 ENST00000683136.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.905
• Publications: 0 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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
• diabetes mellitus, transient neonatal, 2

  Inheritance: AD, Unknown Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), 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: Genomics England PanelApp, Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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)

ENSG00000287898 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000683136.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	NM_000352.6	MANE Select	c.-72G>T		upstream_gene	N/A	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.-72G>T		upstream_gene	N/A	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.-72G>T		upstream_gene	N/A	NP_001274103.1	Q09428-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000683136.1		c.-72G>T		5_prime_UTR	Exon 1 of 38	ENSP00000507768.1	A0A804HK47
	ABCC8	ENST00000644472.1		n.-72G>T		non_coding_transcript_exon	Exon 1 of 21	ENSP00000495378.1	A0A2R8Y698
	ABCC8	ENST00000644675.1		n.-72G>T		non_coding_transcript_exon	Exon 1 of 39	ENSP00000494567.1	A0A2R8YDG6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000361 AC: 4 AN: 1108198 Hom.: 0 Cov.: 30 AF XY: 0.00000567 AC XY: 3 AN XY: 529070

African (AFR) AF: 0.00 AC: 0 AN: 22196

American (AMR) AF: 0.00 AC: 0 AN: 7938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13856

East Asian (EAS) AF: 0.00 AC: 0 AN: 25112

South Asian (SAS) AF: 0.00 AC: 0 AN: 27264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31954

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2962

European-Non Finnish (NFE) AF: 0.00000321 AC: 3 AN: 933140

Other (OTH) AF: 0.0000228 AC: 1 AN: 43776

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.93
PhyloP100		0.91
PromoterAI		-0.29	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs541244107; hg19: chr11-17498395;