rs147623093

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_000352.6(ABCC8):c.1707C>T(p.Ala569Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000766 in 1,614,228 control chromosomes in the GnomAD database, including 7 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 0.00083 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 6 hom. )

Consequence

ABCC8
NM_000352.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:11

Conservation

PhyloP100: -0.196

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 11-17430924-G-A is Benign according to our data. Variant chr11-17430924-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210070.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=7, Uncertain_significance=4}. Variant chr11-17430924-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.196 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.1707C>T	p.Ala569Ala	synonymous_variant	Exon 12 of 39	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.1707C>T	p.Ala569Ala	synonymous_variant	Exon 12 of 39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00127

AC:

318

AN:

251336

Hom.:

AF XY:

0.00119

AC XY:

161

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000704

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000759

AC:

1110

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

547

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.0176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000373

Gnomad4 OTH exome

AF:

0.00217

GnomAD4 genome

AF:

0.000827

AC:

126

AN:

152370

Hom.:

Cov.:

AF XY:

0.000913

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00100

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:2

Jan 25, 2018

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCC8 c.1707C>T alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 251336 control chromosomes, predominantly at a frequency of 0.018 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. This frequency is approximately 5-fold the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Maturity onset diabetes mellitus in young

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs147623093) in MODY yet. -

Permanent neonatal diabetes mellitus

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Transitory neonatal diabetes mellitus

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Hereditary hyperinsulinism

Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 14, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diabetes mellitus, transient neonatal, 2

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diabetes mellitus, permanent neonatal 3

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

7.3

DANN

Benign

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over