rs113873225

Variant names:

• chr11-17406616-G-A
• rs113873225
• NM_000352.6:c.3329+6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000352.6(ABCC8):​c.3329+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,611,936 control chromosomes in the GnomAD database, including 293 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (12 hom., cov: 32)
  • Exomes 𝑓: 0.018 (281 hom.)
• Consequence: ABCC8 NM_000352.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002013
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.518
• Publications: 2 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 (BayesDel_noAF=-0.84).
• BP6: Variant 11-17406616-G-A is Benign according to our data. Variant chr11-17406616-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1929/152264) while in subpopulation NFE AF = 0.0186 (1263/68018). AF 95% confidence interval is 0.0177. There are 12 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR,SD,Unknown 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.3329+6C>T		splice_region intron	N/A	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.3395+6C>T		splice_region intron	N/A	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.3332+6C>T		splice_region intron	N/A	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.3329+6C>T		splice_region intron	N/A	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.3395+6C>T		splice_region intron	N/A	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.3332+6C>T		splice_region intron	N/A	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1931 AN: 152146 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00933

Gnomad FIN AF: 0.0128

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.0114 AC: 2845 AN: 249098 AF XY: 0.0114

Gnomad AFR exome AF: 0.00998

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00560

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.0176

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0178 AC: 26049 AN: 1459672 Hom.: 281 Cov.: 31 AF XY: 0.0172 AC XY: 12459 AN XY: 725766

African (AFR) AF: 0.00754 AC: 252 AN: 33430

American (AMR) AF: 0.00406 AC: 181 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00556 AC: 145 AN: 26090

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39602

South Asian (SAS) AF: 0.00787 AC: 678 AN: 86144

European-Finnish (FIN) AF: 0.0112 AC: 599 AN: 53372

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5764

European-Non Finnish (NFE) AF: 0.0210 AC: 23356 AN: 1110368

Other (OTH) AF: 0.0135 AC: 817 AN: 60296

GnomAD4 genome AF: 0.0127 AC: 1929 AN: 152264 Hom.: 12 Cov.: 32 AF XY: 0.0114 AC XY: 852 AN XY: 74446

African (AFR) AF: 0.00859 AC: 357 AN: 41546

American (AMR) AF: 0.00542 AC: 83 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4818

European-Finnish (FIN) AF: 0.0128 AC: 136 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1263 AN: 68018

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.0159 Hom.: 16

Bravo AF: 0.0123

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0168

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Diabetes mellitus, transient neonatal, 2 (1)
-	-	1	Hereditary hyperinsulinism (1)
-	-	1	Hyperinsulinemic hypoglycemia, familial, 1 (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	-0.84
CADD	Benign	0.41
DANN	Benign	0.46
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0020
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: rs113873225; hg19: chr11-17428163;