rs8192695

Variant names:

• chr11-17470183-G-A
• rs8192695
• NM_000352.6:c.330C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17470183-G-A
• chr11-17470183-G-C
• chr11-17470183-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000352.6(ABCC8):​c.330C>T​(p.Ala110Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 1,614,062 control chromosomes in the GnomAD database, including 2,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (466 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1641 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.61
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-17470183-G-A is Benign according to our data. Variant chr11-17470183-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.330C>T	p.Ala110Ala	synonymous	Exon 3 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.330C>T	p.Ala110Ala	synonymous	Exon 3 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.330C>T	p.Ala110Ala	synonymous	Exon 3 of 39	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.330C>T	p.Ala110Ala	synonymous	Exon 3 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000612903.2	TSL:1	n.231C>T		non_coding_transcript_exon	Exon 3 of 3
	ABCC8	ENST00000644772.1		c.330C>T	p.Ala110Ala	synonymous	Exon 3 of 39	ENSP00000494321.1	A0A2R8Y4V0

Frequencies

GnomAD3 genomes AF: 0.0653 AC: 9929 AN: 152092 Hom.: 462 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0325

Gnomad ASJ AF: 0.0459

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0776

Gnomad FIN AF: 0.0436

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0400

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0448 AC: 11252 AN: 251320 AF XY: 0.0449

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0491

Gnomad EAS exome AF: 0.00658

Gnomad FIN exome AF: 0.0467

Gnomad NFE exome AF: 0.0387

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0432 AC: 63094 AN: 1461852 Hom.: 1641 Cov.: 32 AF XY: 0.0437 AC XY: 31773 AN XY: 727232

African (AFR) AF: 0.134 AC: 4497 AN: 33478

American (AMR) AF: 0.0180 AC: 803 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0468 AC: 1223 AN: 26136

East Asian (EAS) AF: 0.0118 AC: 470 AN: 39696

South Asian (SAS) AF: 0.0697 AC: 6012 AN: 86248

European-Finnish (FIN) AF: 0.0501 AC: 2674 AN: 53410

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5768

European-Non Finnish (NFE) AF: 0.0400 AC: 44532 AN: 1111996

Other (OTH) AF: 0.0458 AC: 2765 AN: 60396

GnomAD4 genome AF: 0.0654 AC: 9960 AN: 152210 Hom.: 466 Cov.: 32 AF XY: 0.0652 AC XY: 4855 AN XY: 74408

African (AFR) AF: 0.134 AC: 5585 AN: 41526

American (AMR) AF: 0.0324 AC: 496 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0459 AC: 159 AN: 3466

East Asian (EAS) AF: 0.00677 AC: 35 AN: 5172

South Asian (SAS) AF: 0.0783 AC: 377 AN: 4816

European-Finnish (FIN) AF: 0.0436 AC: 462 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0400 AC: 2723 AN: 68008

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0465 Hom.: 1001

Bravo AF: 0.0667

Asia WGS AF: 0.0620 AC: 215 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0362

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Type 2 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.7
DANN	Benign	0.77
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs8192695; hg19: chr11-17491730;