rs2077654

Positions:

• chr11-17406354-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000352.6(ABCC8):​c.3329+268G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 524,000 control chromosomes in the GnomAD database, including 14,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (9653 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4759 hom.)
• Consequence: ABCC8 NM_000352.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66

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=-0.86).
• BP6: Variant 11-17406354-C-G is Benign according to our data. Variant chr11-17406354-C-G is described in ClinVar as [Benign]. Clinvar id is 1259658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.3329+268G>C		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+268G>C		intron_variant		1	NM_000352.6	ENSP00000374467	P4

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39349 AN: 151952 Hom.: 9620 Cov.: 32

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.0528

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0962

Gnomad OTH AF: 0.212

GnomAD4 exome AF: 0.123 AC: 45918 AN: 371930 Hom.: 4759 AF XY: 0.121 AC XY: 23482 AN XY: 193504

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.0826

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0948

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.259 AC: 39438 AN: 152070 Hom.: 9653 Cov.: 32 AF XY: 0.258 AC XY: 19152 AN XY: 74346

Gnomad4 AFR AF: 0.650

Gnomad4 AMR AF: 0.166

Gnomad4 ASJ AF: 0.154

Gnomad4 EAS AF: 0.0531

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.0961

Gnomad4 OTH AF: 0.212

Alfa AF: 0.180 Hom.: 748

Bravo AF: 0.278

Asia WGS AF: 0.134 AC: 466 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.23
DANN	Benign	0.60

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: rs2077654; hg19: chr11-17427901;