rs149861153

Variant names:

• chr11-17402699-G-A
• rs149861153
• NM_000352.6:c.3612C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17402699-G-A
• chr11-17402699-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000352.6(ABCC8):​c.3612C>T​(p.Ala1204Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 1,614,228 control chromosomes in the GnomAD database, including 592 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1204A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (131 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (461 hom.)
• Consequence: ABCC8 NM_000352.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.0610
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-17402699-G-A is Benign according to our data. Variant chr11-17402699-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157697.
• BP7: Synonymous conserved (PhyloP=-0.061 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0972 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.3612C>T	p.Ala1204Ala	synonymous	Exon 29 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.3678C>T	p.Ala1226Ala	synonymous	Exon 29 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.3615C>T	p.Ala1205Ala	synonymous	Exon 29 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.3612C>T	p.Ala1204Ala	synonymous	Exon 29 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.3678C>T	p.Ala1226Ala	synonymous	Exon 29 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.3615C>T	p.Ala1205Ala	synonymous	Exon 29 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1932 AN: 152228 Hom.: 129 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00357

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0202 AC: 5082 AN: 251484 AF XY: 0.0156

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.00680 AC: 9938 AN: 1461882 Hom.: 461 Cov.: 33 AF XY: 0.00606 AC XY: 4408 AN XY: 727244

African (AFR) AF: 0.00158 AC: 53 AN: 33480

American (AMR) AF: 0.129 AC: 5749 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.000554 AC: 22 AN: 39700

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86248

European-Finnish (FIN) AF: 0.00154 AC: 82 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00328 AC: 3649 AN: 1112012

Other (OTH) AF: 0.00583 AC: 352 AN: 60396

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152346 Hom.: 131 Cov.: 33 AF XY: 0.0148 AC XY: 1106 AN XY: 74494

African (AFR) AF: 0.00257 AC: 107 AN: 41592

American (AMR) AF: 0.101 AC: 1552 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00357 AC: 243 AN: 68030

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00299 Hom.: 0

Bravo AF: 0.0186

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00231

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (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	-0.72
CADD	Benign	2.6
DANN	Benign	0.49
PhyloP100		-0.061
Mutation Taster		=95/5	polymorphism (auto)

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: rs149861153; hg19: chr11-17424246; COSMIC: COSV56849588; COSMIC: COSV56849588;