rs200091822

Variant names:

• chr11-17476784-C-A
• rs200091822
• NM_000352.6:c.-8G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17476784-C-A
• chr11-17476784-C-G
• chr11-17476784-C-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000352.6(ABCC8):​c.-8G>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 0.00437 in 1,545,004 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (22 hom.)
• Consequence: ABCC8 NM_000352.6 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.65
• 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)

ENSG00000287898 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.128).
• BP6: Variant 11-17476784-C-A is Benign according to our data. Variant chr11-17476784-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255928.
• BS2: High Homozygotes in GnomAdExome4 at 22 AR,AD,Unknown,SD gene

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.-8G>T		5_prime_UTR	Exon 1 of 39	NP_000343.2
	ABCC8	NR_147094.2		n.62G>T		non_coding_transcript_exon	Exon 1 of 38
	ABCC8	NM_001351295.2		c.-8G>T		5_prime_UTR	Exon 1 of 39	NP_001338224.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.-8G>T		5_prime_UTR	Exon 1 of 39	ENSP00000374467.4
	ABCC8	ENST00000524561.2	TSL:5	n.62G>T		non_coding_transcript_exon	Exon 1 of 34
	ABCC8	ENST00000526002.2	TSL:2	n.6G>T		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152012 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00443

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00258 AC: 378 AN: 146580 AF XY: 0.00279

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000445

Gnomad NFE exome AF: 0.00508

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00455 AC: 6341 AN: 1392884 Hom.: 22 Cov.: 31 AF XY: 0.00439 AC XY: 3019 AN XY: 687810

African (AFR) AF: 0.000702 AC: 21 AN: 29928

American (AMR) AF: 0.00178 AC: 63 AN: 35454

Ashkenazi Jewish (ASJ) AF: 0.000162 AC: 4 AN: 24642

East Asian (EAS) AF: 0.00 AC: 0 AN: 34702

South Asian (SAS) AF: 0.00100 AC: 79 AN: 78850

European-Finnish (FIN) AF: 0.000721 AC: 35 AN: 48546

Middle Eastern (MID) AF: 0.000733 AC: 4 AN: 5456

European-Non Finnish (NFE) AF: 0.00548 AC: 5901 AN: 1077632

Other (OTH) AF: 0.00406 AC: 234 AN: 57674

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152120 Hom.: 1 Cov.: 33 AF XY: 0.00253 AC XY: 188 AN XY: 74344

African (AFR) AF: 0.00118 AC: 49 AN: 41550

American (AMR) AF: 0.00222 AC: 34 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10584

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

European-Non Finnish (NFE) AF: 0.00443 AC: 301 AN: 67932

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not specified (3)
-	1	1	not provided (2)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	1	-	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Permanent neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		1.7
PromoterAI		-0.081	Neutral
Mutation Taster		=295/5	polymorphism

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: rs200091822; hg19: chr11-17498331;