rs587783171

Variant names:

• chr11-17395876-A-C
• rs587783171
• NM_000352.6:c.4174T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000352.6(ABCC8):​c.4174T>G​(p.Phe1392Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,446 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1392I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 1 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: Ambry Genetics, Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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
• hypoglycemia, leucine-induced

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• diabetes mellitus, transient neonatal, 2

  Inheritance: Unknown, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 12 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17395876-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 3897812.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 11-17395876-A-C is Pathogenic according to our data. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-17395876-A-C is described in CliVar as Pathogenic. Clinvar id is 157701.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.4174T>G	p.Phe1392Val	missense_variant	Exon 34 of 39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.4174T>G	p.Phe1392Val	missense_variant	Exon 34 of 39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437446 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712148

African (AFR) AF: 0.00 AC: 0 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 41734

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25466

East Asian (EAS) AF: 0.00 AC: 0 AN: 38922

South Asian (SAS) AF: 0.00 AC: 0 AN: 82202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099282

Other (OTH) AF: 0.00 AC: 0 AN: 59458

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000534 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jul 23, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.4	.;.;L;.;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.5	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0030	.;.;D;D;.;.;.;.
Polyphen		0.99	.;.;D;.;.;.;.;.
Vest4		0.92, 0.92
MutPred		0.79		.;.;Loss of stability (P = 0.1712);.;.;.;Loss of stability (P = 0.1712);.;
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs587783171; hg19: chr11-17417423;