11-17443261-T-C

Variant names:

• chr11-17443261-T-C
• rs117874766
• NM_000352.6:c.1384A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000352.6(ABCC8):​c.1384A>G​(p.Ile462Val) variant causes a missense change. The variant allele was found at a frequency of 0.00169 in 1,614,100 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: 4.24
• Publications: 11 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022486657).
• BP6: Variant 11-17443261-T-C is Benign according to our data. Variant chr11-17443261-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210068.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1384A>G	p.Ile462Val	missense	Exon 9 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.1384A>G	p.Ile462Val	missense	Exon 9 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.1384A>G	p.Ile462Val	missense	Exon 9 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.1384A>G	p.Ile462Val	missense	Exon 9 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.1384A>G	p.Ile462Val	missense	Exon 9 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.1384A>G	p.Ile462Val	missense	Exon 9 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152090 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00166

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000875 AC: 220 AN: 251358 AF XY: 0.000869

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00177 AC: 2590 AN: 1461892 Hom.: 6 Cov.: 32 AF XY: 0.00175 AC XY: 1275 AN XY: 727246

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00226 AC: 2508 AN: 1112012

Other (OTH) AF: 0.000911 AC: 55 AN: 60396

GnomAD4 genome AF: 0.000894 AC: 136 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74442

African (AFR) AF: 0.000506 AC: 21 AN: 41530

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00166 AC: 113 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.000914

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.000840 AC: 102

EpiCase AF: 0.00109

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	2	-	not specified (2)
-	1	-	ABCC8-related disorder (1)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	1	-	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	1	-	Pulmonary arterial hypertension (1)
-	1	-	Type 2 diabetes mellitus (1)
-	1	-	Type 2 diabetes mellitus;C2931832:Hyperinsulinemic hypoglycemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.16	N
PhyloP100		4.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.23
Sift	Benign	0.48	T
Sift4G	Benign	0.58	T
Polyphen		0.0050	B
Vest4		0.39
MVP		0.76
MPC		0.22
ClinPred		0.0072	T
GERP RS		4.9
Varity_R		0.12
gMVP		0.53
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs117874766; hg19: chr11-17464808; COSMIC: COSV105132448; COSMIC: COSV105132448;