rs201000679

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

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:3B:3

Conservation

PhyloP100: 0.676

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157708.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6 link	c.823-8C>T		splice_region_variant, intron_variant	Intron 5 of 38	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.823-8C>T		splice_region_variant, intron_variant	Intron 5 of 38	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000371

AC:

AN:

242618

Hom.:

AF XY:

0.0000378

AC XY:

AN XY:

132228

show subpopulations

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 SAS 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:

AN:

1453878

Hom.:

Cov.:

AF XY:

0.00000829

AC XY:

AN XY:

723600

show subpopulations

Gnomad4 AFR exome

AF:

0.000419

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000622

Hom.:

Bravo

AF:

0.000117

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

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

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

DANN

Benign

0.83

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

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