rs113282901

Variant names:

• chr11-17394269-G-T
• rs113282901
• NM_000352.6:c.4542C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000352.6(ABCC8):​c.4542C>A​(p.Ala1514Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,613,816 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (11 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:10
• Conservation: PhyloP100: 0.384
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-17394269-G-T is Benign according to our data. Variant chr11-17394269-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.384 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00457 (696/152302) while in subpopulation AFR AF = 0.0159 (659/41562). AF 95% confidence interval is 0.0149. There are 6 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.4542C>A	p.Ala1514Ala	synonymous	Exon 37 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.4608C>A	p.Ala1536Ala	synonymous	Exon 37 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.4545C>A	p.Ala1515Ala	synonymous	Exon 37 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.4542C>A	p.Ala1514Ala	synonymous	Exon 37 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.4608C>A	p.Ala1536Ala	synonymous	Exon 37 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.4545C>A	p.Ala1515Ala	synonymous	Exon 37 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 681 AN: 152184 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.00

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00107 AC: 268 AN: 251136 AF XY: 0.000736

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000475 AC: 694 AN: 1461514 Hom.: 11 Cov.: 32 AF XY: 0.000426 AC XY: 310 AN XY: 727066

African (AFR) AF: 0.0166 AC: 555 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53126

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5740

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111968

Other (OTH) AF: 0.00131 AC: 79 AN: 60390

GnomAD4 genome AF: 0.00457 AC: 696 AN: 152302 Hom.: 6 Cov.: 33 AF XY: 0.00451 AC XY: 336 AN XY: 74458

African (AFR) AF: 0.0159 AC: 659 AN: 41562

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00206 Hom.: 3

Bravo AF: 0.00527

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Inborn genetic diseases (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	-0.45
CADD	Benign	8.3
DANN	Benign	0.80
PhyloP100		0.38
Mutation Taster		=100/0	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: rs113282901; hg19: chr11-17415816;