rs113873225

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000389817.8(ABCC8):​c.3329+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,611,936 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 12 hom., cov: 32)
Exomes 𝑓: 0.018 ( 281 hom. )

Consequence

ABCC8
ENST00000389817.8 splice_donor_region, intron

Scores

2
Splicing: ADA: 0.00002013
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.518
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BP6
Variant 11-17406616-G-A is Benign according to our data. Variant chr11-17406616-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17406616-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0127 (1929/152264) while in subpopulation NFE AF= 0.0186 (1263/68018). AF 95% confidence interval is 0.0177. There are 12 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCC8NM_000352.6 linkuse as main transcriptc.3329+6C>T splice_donor_region_variant, intron_variant ENST00000389817.8 NP_000343.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCC8ENST00000389817.8 linkuse as main transcriptc.3329+6C>T splice_donor_region_variant, intron_variant 1 NM_000352.6 ENSP00000374467 P4Q09428-1

Frequencies

GnomAD3 genomes
AF:
0.0127
AC:
1931
AN:
152146
Hom.:
12
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00862
Gnomad AMI
AF:
0.00768
Gnomad AMR
AF:
0.00543
Gnomad ASJ
AF:
0.00461
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00933
Gnomad FIN
AF:
0.0128
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0186
Gnomad OTH
AF:
0.00958
GnomAD3 exomes
AF:
0.0114
AC:
2845
AN:
249098
Hom.:
24
AF XY:
0.0114
AC XY:
1529
AN XY:
134630
show subpopulations
Gnomad AFR exome
AF:
0.00998
Gnomad AMR exome
AF:
0.00357
Gnomad ASJ exome
AF:
0.00560
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00715
Gnomad FIN exome
AF:
0.0114
Gnomad NFE exome
AF:
0.0176
Gnomad OTH exome
AF:
0.0112
GnomAD4 exome
AF:
0.0178
AC:
26049
AN:
1459672
Hom.:
281
Cov.:
31
AF XY:
0.0172
AC XY:
12459
AN XY:
725766
show subpopulations
Gnomad4 AFR exome
AF:
0.00754
Gnomad4 AMR exome
AF:
0.00406
Gnomad4 ASJ exome
AF:
0.00556
Gnomad4 EAS exome
AF:
0.0000758
Gnomad4 SAS exome
AF:
0.00787
Gnomad4 FIN exome
AF:
0.0112
Gnomad4 NFE exome
AF:
0.0210
Gnomad4 OTH exome
AF:
0.0135
GnomAD4 genome
AF:
0.0127
AC:
1929
AN:
152264
Hom.:
12
Cov.:
32
AF XY:
0.0114
AC XY:
852
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.00859
Gnomad4 AMR
AF:
0.00542
Gnomad4 ASJ
AF:
0.00461
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00892
Gnomad4 FIN
AF:
0.0128
Gnomad4 NFE
AF:
0.0186
Gnomad4 OTH
AF:
0.00948
Alfa
AF:
0.0167
Hom.:
9
Bravo
AF:
0.0123
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.0163
EpiControl
AF:
0.0168

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 27, 2020This variant is associated with the following publications: (PMID: 23652837) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 03, 2023- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2024ABCC8: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not specified Benign:4
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 06, 2018Variant summary: ABCC8 c.3329+6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.012 in 274898 control chromosomes in the gnomAD database, including 26 homozygotes. The observed variant frequency is approximately 557705.035 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Neonatal Diabetes Mellitus phenotype (2.1e-08), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 22, 2015- -
Hereditary hyperinsulinism Benign:1
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Hyperinsulinemic hypoglycemia, familial, 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 08, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Diabetes mellitus, transient neonatal, 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 08, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Permanent neonatal diabetes mellitus Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 08, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Transitory neonatal diabetes mellitus Benign:1
Benign, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. However, no sufficient evidence is found to ascertain the role of rs113873225 variant in Diabetes Mellitus yet. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
0.41
DANN
Benign
0.46

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000020
dbscSNV1_RF
Benign
0.0020
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.

Other links and lift over

dbSNP: rs113873225; hg19: chr11-17428163; API