rs587783174

Variant names:

• chr11-17460684-G-A
• rs201000679
• NM_000352.6:c.823-8C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000352.6(ABCC8):​c.823-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,606,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ABCC8 NM_000352.6 splice_region, intron
• Scores: Splicing: ADA: 0.004082
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.676
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinemic hypoglycemia, familial, 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial hyperinsulinism

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• diabetes mellitus

  Inheritance: SD Classification: DEFINITIVE Submitted by: Ambry Genetics
• monogenic diabetes

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypoglycemia, leucine-induced

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• diabetes mellitus, transient neonatal, 2

  Inheritance: Unknown, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to SUR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 11-17460684-G-A is Benign according to our data. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708. Variant chr11-17460684-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 157708.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.823-8C>T		splice_region_variant, intron_variant	Intron 5 of 38	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.823-8C>T		splice_region_variant, intron_variant	Intron 5 of 38	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000371 AC: 9 AN: 242618 AF XY: 0.0000378

Gnomad AFR exome AF: 0.000501

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1453878 Hom.: 0 Cov.: 32 AF XY: 0.00000829 AC XY: 6 AN XY: 723600

African (AFR) AF: 0.000419 AC: 14 AN: 33420

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47044

Middle Eastern (MID) AF: 0.000442 AC: 2 AN: 4528

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60212

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74494

African (AFR) AF: 0.000433 AC: 18 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000622 Hom.: 0

Bravo AF: 0.000117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 Uncertain:1

Jan 14, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous c.823-8C>T variant identified in the ABCC8 gene is a non-canonical splicing region variant at the -8 position within intron 5/38. This variant is found with low frequency in gnomAD(v3.1.2)(18 heterozygotes, 0 homozygotes; allele frequency: 1.182e-4) suggesting it is not a common benign variant in the populations represented in that database. In silico splicing algorithms SpliceAI and Transcript inferred Pathogenicity Score (TraP) do not predict this variant has a high probability of altering splicing (SpliceAI delta:0.08 (Acceptor Gain, -8bp); TraP Score 0.038 (25-50% score-percentile)). This variant was reported by a single lab in 2013 as Likely Benign in ClinVar (VarID:157708), although the evidence used for that classification was not available for review. To our current knowledge this variant has not been reported in affected individuals in the literature. Given the lack of compelling evidence for its pathogenicity, the heterozygous c.823-8C>T variant identified in the ABCC8 gene is reported as a Variant of Uncertain Significance. -

Maturity onset diabetes mellitus in young Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs201000679) in MODY yet. -

Transitory neonatal diabetes mellitus Uncertain:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs201000679) in neonatal diabetes yet. -

not specified Benign:1

Oct 29, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC8-related disorder Benign:1

Dec 23, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Feb 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		0.68
PromoterAI		-0.013	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.13
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

Other links and lift over

dbSNP: rs201000679; hg19: chr11-17482231;