rs1799854

Variant names:

• chr11-17427157-G-A
• rs1799854
• NM_000352.6:c.2117-3C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17427157-G-A
• chr11-17427157-G-C
• chr11-17427157-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000352.6(ABCC8):​c.2117-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,608,952 control chromosomes in the GnomAD database, including 148,402 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (12005 hom., cov: 31)
  • Exomes 𝑓: 0.43 (136397 hom.)
• Consequence: ABCC8 NM_000352.6 splice_region, intron
• Scores: Splicing: ADA: 0.1129
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: 2.82
• Publications: 63 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)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 11-17427157-G-A is Benign according to our data. Variant chr11-17427157-G-A is described in ClinVar as Benign. ClinVar VariationId is 157688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	NM_000352.6	MANE Select	c.2117-3C>T		splice_region intron	N/A	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.2183-3C>T		splice_region intron	N/A	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.2117-3C>T		splice_region intron	N/A	NP_001274103.1	Q09428-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.2117-3C>T		splice_region intron	N/A	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.2183-3C>T		splice_region intron	N/A	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.2117-3C>T		splice_region intron	N/A	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56513 AN: 151924 Hom.: 11999 Cov.: 31

Gnomad AFR AF: 0.167

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.406

GnomAD2 exomes AF: 0.440 AC: 108736 AN: 246958 AF XY: 0.433

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.596

Gnomad FIN exome AF: 0.431

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.427 AC: 622485 AN: 1456910 Hom.: 136397 Cov.: 36 AF XY: 0.425 AC XY: 308010 AN XY: 724320

African (AFR) AF: 0.158 AC: 5295 AN: 33428

American (AMR) AF: 0.597 AC: 26467 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 11888 AN: 26012

East Asian (EAS) AF: 0.540 AC: 21346 AN: 39502

South Asian (SAS) AF: 0.328 AC: 28159 AN: 85730

European-Finnish (FIN) AF: 0.433 AC: 22833 AN: 52672

Middle Eastern (MID) AF: 0.397 AC: 2281 AN: 5750

European-Non Finnish (NFE) AF: 0.431 AC: 478352 AN: 1109296

Other (OTH) AF: 0.430 AC: 25864 AN: 60170

GnomAD4 genome AF: 0.372 AC: 56535 AN: 152042 Hom.: 12005 Cov.: 31 AF XY: 0.374 AC XY: 27762 AN XY: 74284

African (AFR) AF: 0.167 AC: 6910 AN: 41488

American (AMR) AF: 0.499 AC: 7624 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1580 AN: 3472

East Asian (EAS) AF: 0.565 AC: 2908 AN: 5148

South Asian (SAS) AF: 0.346 AC: 1664 AN: 4814

European-Finnish (FIN) AF: 0.436 AC: 4607 AN: 10556

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.438 AC: 29765 AN: 67974

Other (OTH) AF: 0.404 AC: 850 AN: 2106

Alfa AF: 0.425 Hom.: 25070

Bravo AF: 0.373

Asia WGS AF: 0.404 AC: 1409 AN: 3478

EpiCase AF: 0.441

EpiControl AF: 0.442

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Diabetes mellitus, transient neonatal, 2 (2)
-	-	2	Hyperinsulinemic hypoglycemia, familial, 1 (2)
-	-	1	Diabetes mellitus, permanent neonatal 3 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Leucine-induced hypoglycemia (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 (1)
-	-	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		2.8
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.020		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: rs1799854; hg19: chr11-17448704; COSMIC: COSV107400438; COSMIC: COSV107400438;