rs587783164

Variant names:

• chr11-17448511-AG-A
• rs587783164
• NM_000352.6:c.1332+4delC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_001351295.2(ABCC8):​c.1332+4delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: ABCC8 NM_001351295.2 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.539
• Publications: 3 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 -8 ACMG points.

• BP6: Variant 11-17448511-AG-A is Benign according to our data. Variant chr11-17448511-AG-A is described in ClinVar as Likely_benign. ClinVar VariationId is 157682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351295.2. 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.1332+4delC		splice_region intron	N/A	NP_000343.2
	ABCC8	NM_001351295.2		c.1332+4delC		splice_region intron	N/A	NP_001338224.1
	ABCC8	NM_001287174.3		c.1332+4delC		splice_region intron	N/A	NP_001274103.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.1332+4delC		splice_region intron	N/A	ENSP00000374467.4
	ABCC8	ENST00000644772.1		c.1332+4delC		splice_region intron	N/A	ENSP00000494321.1
	ABCC8	ENST00000302539.9	TSL:5	c.1332+4delC		splice_region intron	N/A	ENSP00000303960.4

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00201

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000970 AC: 244 AN: 251448 AF XY: 0.000920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00156

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00129 AC: 1878 AN: 1461464 Hom.: 0 Cov.: 30 AF XY: 0.00124 AC XY: 900 AN XY: 727066

African (AFR) AF: 0.000209 AC: 7 AN: 33472

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00152 AC: 1687 AN: 1111626

Other (OTH) AF: 0.00103 AC: 62 AN: 60380

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74392

African (AFR) AF: 0.000193 AC: 8 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00201 AC: 137 AN: 68006

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.000722

EpiCase AF: 0.00109

EpiControl AF: 0.000889

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Hyperinsulinism, Dominant/Recessive (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Transient Neonatal Diabetes, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587783164; hg19: chr11-17470058;