chr11-17396930-C-A

Variant names:

• chr11-17396930-C-A
• rs757110
• NM_000352.6:c.4105G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000352.6(ABCC8):​c.4105G>T​(p.Ala1369Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,778 control chromosomes in the GnomAD database, including 341,651 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1369T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.71 (40061 hom., cov: 34)
  • Exomes 𝑓: 0.64 (301590 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.0710
• Publications: 229 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2142411E-6).
• BP6: Variant 11-17396930-C-A is Benign according to our data. Variant chr11-17396930-C-A is described in ClinVar as Benign. ClinVar VariationId is 157699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.926 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.4105G>T	p.Ala1369Ser	missense	Exon 33 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.4171G>T	p.Ala1391Ser	missense	Exon 33 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.4108G>T	p.Ala1370Ser	missense	Exon 33 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.4105G>T	p.Ala1369Ser	missense	Exon 33 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.4171G>T	p.Ala1391Ser	missense	Exon 33 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.4108G>T	p.Ala1370Ser	missense	Exon 33 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108208 AN: 151974 Hom.: 40001 Cov.: 34

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.624

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.688

GnomAD2 exomes AF: 0.636 AC: 159547 AN: 251040 AF XY: 0.630

Gnomad AFR exome AF: 0.939

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.611

Gnomad EAS exome AF: 0.621

Gnomad FIN exome AF: 0.519

Gnomad NFE exome AF: 0.630

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.640 AC: 935098 AN: 1461686 Hom.: 301590 Cov.: 70 AF XY: 0.637 AC XY: 463383 AN XY: 727148

African (AFR) AF: 0.947 AC: 31692 AN: 33480

American (AMR) AF: 0.624 AC: 27907 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 16107 AN: 26134

East Asian (EAS) AF: 0.614 AC: 24390 AN: 39698

South Asian (SAS) AF: 0.618 AC: 53298 AN: 86252

European-Finnish (FIN) AF: 0.522 AC: 27830 AN: 53334

Middle Eastern (MID) AF: 0.713 AC: 4110 AN: 5764

European-Non Finnish (NFE) AF: 0.639 AC: 710443 AN: 1111934

Other (OTH) AF: 0.651 AC: 39321 AN: 60384

GnomAD4 genome AF: 0.712 AC: 108332 AN: 152092 Hom.: 40061 Cov.: 34 AF XY: 0.706 AC XY: 52448 AN XY: 74332

African (AFR) AF: 0.934 AC: 38764 AN: 41522

American (AMR) AF: 0.670 AC: 10237 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.624 AC: 2166 AN: 3472

East Asian (EAS) AF: 0.630 AC: 3252 AN: 5158

South Asian (SAS) AF: 0.609 AC: 2936 AN: 4820

European-Finnish (FIN) AF: 0.530 AC: 5612 AN: 10584

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43271 AN: 67928

Other (OTH) AF: 0.688 AC: 1454 AN: 2114

Alfa AF: 0.656 Hom.: 161218

Bravo AF: 0.728

TwinsUK AF: 0.648 AC: 2404

ALSPAC AF: 0.633 AC: 2440

ESP6500AA AF: 0.932 AC: 4101

ESP6500EA AF: 0.639 AC: 5490

ExAC AF: 0.643 AC: 78021

Asia WGS AF: 0.651 AC: 2263 AN: 3478

EpiCase AF: 0.636

EpiControl AF: 0.637

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Diabetes mellitus, permanent neonatal 3 (1)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (1)
-	-	1	Hyperinsulinism, Dominant/Recessive (1)
-	-	1	Leucine-induced hypoglycemia (1)
-	-	1	Permanent neonatal diabetes mellitus (1)
-	-	1	Transient Neonatal Diabetes, Dominant (1)
-	-	1	Type 2 diabetes mellitus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	2.4
DANN	Benign	0.16
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
PhyloP100		-0.071
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.98	N
REVEL	Uncertain	0.51
Sift	Benign	0.41	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.64
ClinPred		0.00031	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757110; hg19: chr11-17418477; COSMIC: COSV56856755; COSMIC: COSV56856755;