rs1805036

Positions:

• chr11-17412737-G-A
• chr11-17412737-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000352.6(ABCC8):​c.2485C>T​(p.Leu829Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,609,174 control chromosomes in the GnomAD database, including 10,160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2007 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8153 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.04

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-17412737-G-A is Benign according to our data. Variant chr11-17412737-G-A is described in ClinVar as [Benign]. Clinvar id is 157691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17412737-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.2485C>T	p.Leu829Leu	synonymous_variant	21/39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.2485C>T	p.Leu829Leu	synonymous_variant	21/39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21340 AN: 151988 Hom.: 2004 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0865

Gnomad ASJ AF: 0.0814

Gnomad EAS AF: 0.0296

Gnomad SAS AF: 0.0667

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0978

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.0966 AC: 23353 AN: 241778 Hom.: 1470 AF XY: 0.0955 AC XY: 12456 AN XY: 130476

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.0834

Gnomad EAS exome AF: 0.0300

Gnomad SAS exome AF: 0.0747

Gnomad FIN exome AF: 0.146

Gnomad NFE exome AF: 0.0968

Gnomad OTH exome AF: 0.0982

GnomAD4 exome AF: 0.100 AC: 146110 AN: 1457068 Hom.: 8153 Cov.: 32 AF XY: 0.0987 AC XY: 71513 AN XY: 724208

Gnomad4 AFR exome AF: 0.263

Gnomad4 AMR exome AF: 0.0536

Gnomad4 ASJ exome AF: 0.0877

Gnomad4 EAS exome AF: 0.0281

Gnomad4 SAS exome AF: 0.0769

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.0994

GnomAD4 genome AF: 0.140 AC: 21356 AN: 152106 Hom.: 2007 Cov.: 32 AF XY: 0.139 AC XY: 10375 AN XY: 74374

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.0864

Gnomad4 ASJ AF: 0.0814

Gnomad4 EAS AF: 0.0295

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.0978

Gnomad4 OTH AF: 0.123

Alfa AF: 0.102 Hom.: 2047

Bravo AF: 0.142

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Diabetes mellitus, transient neonatal, 2 Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

Neonatal hypoglycemia Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

rs1805036 variant of ABCC8 gene is associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may respond to sulfonylureas. -

Hereditary hyperinsulinism Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Leucine-induced hypoglycemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Diabetes mellitus, permanent neonatal 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jul 01, 2021

- -

Permanent neonatal diabetes mellitus Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.0
DANN	Benign	0.75

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

Other links and lift over

dbSNP: rs1805036; hg19: chr11-17434284; COSMIC: COSV56859671;