rs113873225

Positions:

• chr11-17406616-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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: Splicing: ADA: 0.00002013
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.518

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]

ACMG classification

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
ABCC8	NM_000352.6	c.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
ABCC8	ENST00000389817.8	c.3329+6C>T		splice_donor_region_variant, intron_variant		1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1931 AN: 152146 Hom.: 12 Cov.: 32

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

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

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

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

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	This variant is associated with the following publications: (PMID: 23652837) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	ABCC8: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2018	Variant 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 submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Hyperinsulinemic hypoglycemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

This 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 submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

This 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 submitter

research

Clinical 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

Other links and lift over

dbSNP: rs113873225; hg19: chr11-17428163;