11-17428382-C-T

Variant names:

• chr11-17428382-C-T
• rs1799858
• NM_000352.6:c.1947G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_000352.6(ABCC8):​c.1947G>A​(p.Lys649Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,613,742 control chromosomes in the GnomAD database, including 22,375 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 0.17 (2216 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20159 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 1.86
• Publications: 30 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-17428382-C-T is Benign according to our data. Variant chr11-17428382-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157686.
• BP7: Synonymous conserved (PhyloP=1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

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.1947G>A	p.Lys649Lys	synonymous	Exon 14 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.2013G>A	p.Lys671Lys	synonymous	Exon 14 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.1947G>A	p.Lys649Lys	synonymous	Exon 14 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.1947G>A	p.Lys649Lys	synonymous	Exon 14 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.2013G>A	p.Lys671Lys	synonymous	Exon 14 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.1947G>A	p.Lys649Lys	synonymous	Exon 14 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25218 AN: 152044 Hom.: 2214 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.151

GnomAD2 exomes AF: 0.174 AC: 43615 AN: 250856 AF XY: 0.178

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.126

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.197

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.163

GnomAD4 exome AF: 0.160 AC: 233646 AN: 1461580 Hom.: 20159 Cov.: 33 AF XY: 0.163 AC XY: 118674 AN XY: 727072

African (AFR) AF: 0.181 AC: 6062 AN: 33478

American (AMR) AF: 0.131 AC: 5862 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4869 AN: 26134

East Asian (EAS) AF: 0.199 AC: 7906 AN: 39688

South Asian (SAS) AF: 0.280 AC: 24168 AN: 86246

European-Finnish (FIN) AF: 0.198 AC: 10565 AN: 53330

Middle Eastern (MID) AF: 0.118 AC: 683 AN: 5766

European-Non Finnish (NFE) AF: 0.147 AC: 163508 AN: 1111846

Other (OTH) AF: 0.166 AC: 10023 AN: 60376

GnomAD4 genome AF: 0.166 AC: 25250 AN: 152162 Hom.: 2216 Cov.: 33 AF XY: 0.171 AC XY: 12737 AN XY: 74382

African (AFR) AF: 0.178 AC: 7379 AN: 41514

American (AMR) AF: 0.158 AC: 2417 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3472

East Asian (EAS) AF: 0.199 AC: 1028 AN: 5162

South Asian (SAS) AF: 0.289 AC: 1391 AN: 4812

European-Finnish (FIN) AF: 0.189 AC: 2000 AN: 10596

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9910 AN: 67998

Other (OTH) AF: 0.155 AC: 328 AN: 2114

Alfa AF: 0.151 Hom.: 1310

Bravo AF: 0.159

Asia WGS AF: 0.292 AC: 1013 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.140

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hyperinsulinemic hypoglycemia, familial, 1 (3)
-	-	3	not specified (3)
-	-	2	Diabetes mellitus, transient neonatal, 2 (2)
-	-	2	not provided (2)
-	-	1	Diabetes mellitus, permanent neonatal 3 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Leucine-induced hypoglycemia (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	1	-	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_noAF	Benign	-0.34
CADD	Benign	7.4
DANN	Benign	0.60
PhyloP100		1.9
PromoterAI		0.0068	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1799858; hg19: chr11-17449929; COSMIC: COSV56849597; COSMIC: COSV56849597;