rs58241708

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). Synonymous variant affecting the same amino acid position (i.e. R620R) has been classified as Likely benign.

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:

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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: {Benign=2, Likely_benign=5, 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 GnomAd at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.1858C>T	p.Arg620Cys	missense_variant	13/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.1858C>T	p.Arg620Cys	missense_variant	13/39	1	NM_000352.6	P4	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

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	This variant is associated with the following publications: (PMID: 31604004, 23275527, 28095440, 22995991, 22210575, 20849526, 10204114, 20981092, 23771920) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 05, 2018	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 29, 2022	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 0.00069 in 251124 control chromosomes, predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1858C>T has been reported in the literature as a non-informative genotype (unclear inheritance pattern) in settings of Familial Hyperinsulinism, Adult onset Type 2 diabetes and Gestational Diabetes (example, Lang_2010, Riveleine_2012, Doddabelavangala Mruthyunjaya_2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with a predominant consensus as benign/likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 19, 2015	- -

Hereditary hyperinsulinism

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 24, 2019

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Dec 07, 2018

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

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.37

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