rs886292

Variant names:

• chr11-17444498-A-C
• rs886292
• NM_000352.6:c.1333-1186T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-17444498-A-C
• chr11-17444498-A-T

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.1333-1186T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 152,066 control chromosomes in the GnomAD database, including 13,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13529 hom., cov: 31)
  • Exomes 𝑓: 0.39 (19 hom.)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.593
• Publications: 5 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=-0.92).
• BP6: Variant 11-17444498-A-C is Benign according to our data. Variant chr11-17444498-A-C is described in ClinVar as Benign. ClinVar VariationId is 1246345.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000352.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	NM_000352.6	MANE Select	c.1333-1186T>G		intron	N/A	NP_000343.2
	ABCC8	NM_001351295.2		c.1333-1186T>G		intron	N/A	NP_001338224.1
	ABCC8	NM_001287174.3		c.1333-1186T>G		intron	N/A	NP_001274103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.1333-1186T>G		intron	N/A	ENSP00000374467.4
	ABCC8	ENST00000682185.1		n.1452T>G		non_coding_transcript_exon	Exon 1 of 31
	ABCC8	ENST00000644772.1		c.1333-1186T>G		intron	N/A	ENSP00000494321.1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61593 AN: 151748 Hom.: 13513 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.422

GnomAD4 exome AF: 0.385 AC: 77 AN: 200 Hom.: 19 AF XY: 0.361 AC XY: 57 AN XY: 158

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.667 AC: 4 AN: 6

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.409 AC: 67 AN: 164

Other (OTH) AF: 0.00 AC: 0 AN: 10

GnomAD4 genome AF: 0.406 AC: 61653 AN: 151866 Hom.: 13529 Cov.: 31 AF XY: 0.397 AC XY: 29482 AN XY: 74226

African (AFR) AF: 0.578 AC: 23932 AN: 41402

American (AMR) AF: 0.395 AC: 6028 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1514 AN: 3468

East Asian (EAS) AF: 0.284 AC: 1456 AN: 5132

South Asian (SAS) AF: 0.231 AC: 1110 AN: 4812

European-Finnish (FIN) AF: 0.246 AC: 2594 AN: 10556

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23650 AN: 67924

Other (OTH) AF: 0.418 AC: 881 AN: 2108

Alfa AF: 0.209 Hom.: 384

Bravo AF: 0.428

Asia WGS AF: 0.269 AC: 937 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.82
DANN	Benign	0.63
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs886292; hg19: chr11-17466045; COSMIC: COSV56858385; COSMIC: COSV56858385;