rs60637558

Positions:

chr11-17470138-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000352.6(ABCC8):c.375C>G(p.His125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.32

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.375C>G	p.His125Gln	missense_variant	3/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.375C>G	p.His125Gln	missense_variant	3/39	1	NM_000352.6	ENSP00000374467	P4	Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251420

Hom.:

AF XY:

0.0000956

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

172

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000129

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 11, 2022

Variant summary: ABCC8 c.375C>G (p.His125Gln) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251620 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (8.7e-05 vs 0.0034), allowing no conclusion about variant significance. c.375C>G has been reported in the literature in individuals affected with Congenital Hyperinsulinism or monogenic diabetes. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant affects macroscopic channel activity in intact cells and channel activity in the absence of ATP. However, this variant does not affect the channel activity response to ATP significantly (Shyng_1998). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=3). Based on the evidence outlined above, the variant was classified as VUS. -

Type 2 diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 05, 2023

- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Sep 23, 2016

ACMG Criteria:PP3, PS3 (Shyng et al performed functional analysis in PMID 9648840), Nestorowicz et al describes in single hyperinsulinemic patient PMID 9618169 -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 28, 2018

- -

Permanent neonatal diabetes mellitus

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

.;M;M;M;.;.;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.92, 0.93

MutPred

0.75

Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);

MVP

0.96

MPC

0.92

ClinPred

0.69

GERP RS

3.9

Varity_R

0.82

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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