rs72559716

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000352.6(ABCC8):c.4411G>C(p.Asp1471His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91

Variant links:

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 links:

ABCC8 (HGNC:):

ABCC8 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

PP5

Variant 11-17395172-C-G is Pathogenic according to our data. Variant chr11-17395172-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1452717.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCC8	NM_000352.6 linkuse as main transcript	c.4411G>C	p.Asp1471His	missense_variant, splice_region_variant	36/39	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4411G>C	p.Asp1471His	missense_variant, splice_region_variant	36/39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1417356

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

700790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.20e-7

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 04, 2021

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp1471 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17466004, 18988933, 30352420, 30354297). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (ExAC no frequency). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects ABCC8 protein function (PMID: 17575084). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is also known as p.Asp1472His. This variant has been observed in individuals with congenital hyperinsulinism (PMID: 15562009, 23275527). This sequence change replaces aspartic acid with histidine at codon 1471 of the ABCC8 protein (p.Asp1471His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant also falls at the last nucleotide of exon 36, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

.;.;D;.;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.5

.;.;M;.;.;.;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.7

.;.;D;D;.;.;.;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

.;.;D;D;.;.;.;.

Sift4G

Pathogenic

0.0010

.;.;D;D;.;.;.;.

Polyphen

0.99

.;.;D;.;.;.;.;.

Vest4

0.98, 0.98

MutPred

0.91

.;.;Gain of disorder (P = 0.1259);.;.;.;Gain of disorder (P = 0.1259);.;

MVP

0.94

MPC

1.3

ClinPred

0.99

GERP RS

5.4

Varity_R

0.81

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.87

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over