rs28938469

Variant names:

• chr11-17395659-G-A
• rs28938469
• NM_000352.6:c.4258C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-17395659-G-A
• chr11-17395659-G-T
• chr11-17395659-G-C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000352.6(ABCC8):​c.4258C>T​(p.Arg1420Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000994 in 1,408,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915514: Matsuo et al. (2000) analyzed the functional effect of the p.Arg1420Cys variant and showed it lowers affinity for ATP and ADP binding and leads to enhanced insulin secretion. Tanizawa et al. (2000) transiently expressed the variant protein in COS-7 cells and showed inhibition of channel formation and function compared to wild type." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1420H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.18
• Publications: 19 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: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915514: Matsuo et al. (2000) analyzed the functional effect of the p.Arg1420Cys variant and showed it lowers affinity for ATP and ADP binding and leads to enhanced insulin secretion. Tanizawa et al. (2000) transiently expressed the variant protein in COS-7 cells and showed inhibition of channel formation and function compared to wild type.; SCV006322970: Relevant functional assessments of this variant are available in the literature (PMID: 10993895, 10615958, 26246406).; SCV001407856: Experimental studies have shown that this missense change affects ABCC8 function (PMID: 10615958, 10993895, 26246406).; SCV005325034: Published functional studies demonstrate a damaging effect and show that this variant leads to channel function impairment (Tanizawa et al., 2000; Matsuo et al., 2000; Baier et al., 2015)
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000352.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17395658-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2576195.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 11-17395659-G-A is Pathogenic according to our data. Variant chr11-17395659-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4258C>T	p.Arg1420Cys	missense	Exon 35 of 39	NP_000343.2	Q09428-1
	ABCC8	NM_001351295.2		c.4324C>T	p.Arg1442Cys	missense	Exon 35 of 39	NP_001338224.1	A0A2R8Y4V0
	ABCC8	NM_001287174.3		c.4261C>T	p.Arg1421Cys	missense	Exon 35 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.4258C>T	p.Arg1420Cys	missense	Exon 35 of 39	ENSP00000374467.4	Q09428-1
	ABCC8	ENST00000644772.1		c.4324C>T	p.Arg1442Cys	missense	Exon 35 of 39	ENSP00000494321.1	A0A2R8Y4V0
	ABCC8	ENST00000302539.9	TSL:5	c.4261C>T	p.Arg1421Cys	missense	Exon 35 of 39	ENSP00000303960.4	Q09428-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000994 AC: 14 AN: 1408732 Hom.: 0 Cov.: 31 AF XY: 0.0000101 AC XY: 7 AN XY: 695626

African (AFR) AF: 0.00 AC: 0 AN: 32266

American (AMR) AF: 0.00 AC: 0 AN: 36812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25248

East Asian (EAS) AF: 0.00 AC: 0 AN: 36816

South Asian (SAS) AF: 0.00 AC: 0 AN: 79834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1084504

Other (OTH) AF: 0.0000171 AC: 1 AN: 58416

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hyperinsulinemic hypoglycemia, familial, 1 (5)
2	-	-	not provided (2)
1	-	-	Hereditary hyperinsulinism (1)
1	-	-	Type 2 diabetes mellitus (1)
1	-	-	Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.86		Loss of methylation at R1420 (P = 0.0376)
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.94
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28938469; hg19: chr11-17417206; COSMIC: COSV56847151; COSMIC: COSV56847151;