NM_000352.6:c.1158C>T

Variant names:

• chr11-17453137-G-A
• rs60824529
• NM_000352.6:c.1158C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000352.6(ABCC8):​c.1158C>T​(p.Asn386Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00228 in 1,614,004 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.013 (42 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (38 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 5.70
• Publications: 4 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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
• diabetes mellitus, transient neonatal, 2

  Inheritance: AD, Unknown Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), 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: Genomics England PanelApp, Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-17453137-G-A is Benign according to our data. Variant chr11-17453137-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157681.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0126 (1919/152244) while in subpopulation AFR AF = 0.0441 (1830/41534). AF 95% confidence interval is 0.0424. There are 42 homozygotes in GnomAd4. There are 882 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 AR,AD,Unknown,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000352.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	NM_000352.6	MANE Select	c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	NP_001274103.1	Q09428-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCC8	ENST00000389817.8	TSL:1 MANE Select	c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.1158C>T	p.Asn386Asn	synonymous	Exon 7 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1916 AN: 152126 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.000162

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00336 AC: 844 AN: 251478 AF XY: 0.00244

Gnomad AFR exome AF: 0.0475

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00121 AC: 1763 AN: 1461760 Hom.: 38 Cov.: 31 AF XY: 0.00103 AC XY: 746 AN XY: 727172

African (AFR) AF: 0.0429 AC: 1436 AN: 33470

American (AMR) AF: 0.00154 AC: 69 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000773 AC: 86 AN: 1111900

Other (OTH) AF: 0.00248 AC: 150 AN: 60394

GnomAD4 genome AF: 0.0126 AC: 1919 AN: 152244 Hom.: 42 Cov.: 32 AF XY: 0.0119 AC XY: 882 AN XY: 74418

African (AFR) AF: 0.0441 AC: 1830 AN: 41534

American (AMR) AF: 0.00360 AC: 55 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00497 Hom.: 28

Bravo AF: 0.0141

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	1	-	Maturity-onset diabetes of the young (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	1	-	Transitory neonatal diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.6
DANN	Benign	0.72
PhyloP100		5.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs60824529; hg19: chr11-17474684;