rs8192695

Positions:

• chr11-17470183-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 157695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17470183-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.330C>T	p.Ala110Ala	synonymous_variant	3/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.330C>T	p.Ala110Ala	synonymous_variant	3/39	1	NM_000352.6	ENSP00000374467.4

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

GnomAD3 exomes AF: 0.0448 AC: 11252 AN: 251320 Hom.: 375 AF XY: 0.0449 AC XY: 6102 AN XY: 135858

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 SAS exome AF: 0.0707

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

Gnomad4 AFR exome AF: 0.134

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.0697

Gnomad4 FIN exome AF: 0.0501

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0458

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

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0324

Gnomad4 ASJ AF: 0.0459

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.0783

Gnomad4 FIN AF: 0.0436

Gnomad4 NFE AF: 0.0400

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0429 Hom.: 415

Bravo AF: 0.0667

Asia WGS AF: 0.0620 AC: 215 AN: 3478

EpiCase AF: 0.0384

EpiControl AF: 0.0362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Type 2 diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in ABCC8 gene are generally associated with both neonatal diabetes mellitus as well as MODY. rs8192695 in particular, is associated with cardiovascular events in T2DM patients. Patients with this mutation may also respond to sulfonylureas. -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 27, 2022

- -

Diabetes mellitus, transient neonatal, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Permanent neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.7
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs8192695; hg19: chr11-17491730;