rs58241708

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000352.6(ABCC8):c.1858C>T(p.Arg620Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000496 in 1,613,976 control chromosomes in the GnomAD database, including 5 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 0.0025 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 5.64

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008873194).

BP6

Variant 11-17428630-G-A is Benign according to our data. Variant chr11-17428630-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210071.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr11-17428630-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00249 (380/152320) while in subpopulation AFR AF= 0.00871 (362/41568). AF 95% confidence interval is 0.00797. There are 4 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.1858C>T	p.Arg620Cys	missense_variant	Exon 13 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.1858C>T	p.Arg620Cys	missense_variant	Exon 13 of 39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.00249

AC:

379

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00871

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000693

AC:

174

AN:

251124

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00935

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000288

AC:

421

AN:

1461656

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

162

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00983

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.00249

AC:

380

AN:

152320

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00871

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.00306

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCC8 p.Arg620Cys variant was identified in 2 of 378 proband chromosomes (frequency: 0.0053) from individuals or families with Maturity Onset Diabetes of the Young (MODY) or Type 2 diabetes (Doddabelavangala_2017_PMID:28095440; Riveline_2012_PMID:22210575). The variant was also identified in dbSNP (ID: rs58241708), ClinVar (classified as likely benign by Genetic Services Laboratory, University of Chicago and as a VUS by Counsyl) and LOVD 3.0. The variant was identified in control databases in 253 of 282492 chromosomes (1 homozygous) at a frequency of 0.000896 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 231 of 24964 chromosomes (freq: 0.009253), Latino in 10 of 35424 chromosomes (freq: 0.000282), Other in 2 of 7222 chromosomes (freq: 0.000277), Ashkenazi Jewish in 2 of 10360 chromosomes (freq: 0.000193), South Asian in 5 of 30616 chromosomes (freq: 0.000163) and European (non-Finnish) in 3 of 129052 chromosomes (freq: 0.000023), while the variant was not observed in the East Asian or European (Finnish) populations. The p.Arg620 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 03, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31604004, 23275527, 28095440, 22995991, 22210575, 20849526, 10204114, 20981092, 23771920) -

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:1Benign:1

Jan 05, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Oct 04, 2024

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCC8 c.1858C>T (p.Arg620Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 1607004 control chromosomes, predominantly at a frequency of 0.0092 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.74 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism phenotype (0.0034). The variant, c.1858C>T, has been reported in the literature in individuals affected with diabetes, including adult-onset type 2 diabetes and gestational diabetes (e.g. Lang_2010, Riveleine_2012, Doddabelavangala Mruthyunjaya_2017), and in a child with Congenital Hyperinsulinism, who also carried a second pathogenic variant (Snider_2013), however no supportive evidence for causality was provided. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28095440, 23226049, 22210575, 23275527). ClinVar contains an entry for this variant (Variation ID: 210071). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hyperinsulinism

Benign:1

Dec 24, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Monogenic diabetes

Benign:1

Dec 07, 2018

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria: BS2 (23 cases and 24 controls in type2diabetesgenetics.org) + BS1 (0.9% MAF in gnomAD African pop) = benign (REVEL 0.445 + PP3/8 predictors + BP4/2 predictors = conflicting evidence, not using). Variant found in 46-year old male with T2DM, not overweight, treated with SU (PMID: 22210575); Reported to cause HI of infancy (AR) in summary table in PMID 23226049 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

.;.;D;.;.;.;.

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;.;D;D;D;D;D

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T

MetaSVM

Uncertain

0.085

MutationAssessor

Benign

1.5

.;L;L;L;.;.;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.2

.;.;N;N;.;.;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.025

.;.;D;D;.;.;.

Sift4G

Uncertain

0.013

.;.;D;D;.;.;.

Polyphen

0.84

.;.;P;.;.;.;.

Vest4

0.76, 0.81

MVP

0.88

MPC

0.38

ClinPred

0.027

GERP RS

4.3

Varity_R

0.12

gMVP

0.48

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