chr2-43852692-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5BP4

The NM_022437.3(ABCG8):c.788G>A(p.Arg263Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R263W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000063 ( 0 hom. )

Consequence

ABCG8
NM_022437.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 9.51

Publications

20 publications found

Variant links:

Genes affected

ABCG8 (HGNC:13887): (ATP binding cassette subfamily G 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 White subfamily. The protein encoded by this gene functions to exclude non-cholesterol sterol entry at the intestinal level, promote excretion of cholesterol and sterols into bile, and to facilitate transport of sterols back into the intestinal lumen. It is expressed in a tissue-specific manner in the liver, intestine, and gallbladder. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG5. Mutations in this gene may contribute to sterol accumulation and atherosclerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG8 Gene-Disease associations (from GenCC):

sitosterolemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Illumina
sitosterolemia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP5

Variant 2-43852692-G-A is Pathogenic according to our data. Variant chr2-43852692-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4970.

BP4

Computational evidence support a benign effect (MetaRNN=0.19293183). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.788G>A	p.Arg263Gln	missense_variant	Exon 6 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.788G>A	p.Arg263Gln	missense_variant	Exon 6 of 13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.788G>A	p.Arg263Gln	missense_variant	Exon 6 of 13	1	NM_022437.3	ENSP00000272286.2		Q9H221-1
ABCG8	ENST00000644611.1 link	c.800G>A	p.Arg267Gln	missense_variant	Exon 6 of 9			ENSP00000495423.1		A0A2R8Y6M1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000143

AC:

AN:

251412

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000629

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000680

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000450

AC:

AN:

1112008

Other (OTH)

AF:

0.000182

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000917

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Sitosterolemia 1

Pathogenic:1Uncertain:1

Dec 30, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1Uncertain:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 263 of the ABCG8 protein (p.Arg263Gln). This variant is present in population databases (rs137852990, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of sitosterolemia (PMID: 11452359, 24166850, 24657386, 29886606; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4970). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ABCG8 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jul 03, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCG8-related disorder

Pathogenic:1

Mar 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCG8 c.788G>A variant is predicted to result in the amino acid substitution p.Arg263Gln. This variant has been reported in the compound heterozygous state with a truncating ABCG8 variant in an individual with sitosterolemia (Wang et al. 2014. PubMed ID: 24166850). This variant has also been reported in individuals with sitosterolemia (phytosterolemia) or familial hypercholesterolemia (Berge et al. 2000. PubMed ID: 11099417; Hansel et al. 2014. PubMed ID: 24657386; Reeskamp et al. 2020. PubMed ID: 32088153). This variant is reported in 0.13% of alleles in individuals of East Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Nov 14, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R263Q variant (also known as c.788G>A), located in coding exon 6 of the ABCG8 gene, results from a G to A substitution at nucleotide position 788. The arginine at codon 263 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in the homozygous state and/or in conjunction with other ABCG8 variant(s) in individual(s) with features consistent with sitosterolemia; in at least one instance, the variants were identified in trans (Hansel B et al. Atherosclerosis, 2014 May;234:162-8; Wang Z et al. Am J Hematol, 2014 Mar;89:320-4; Helgadottir A et al. Eur Heart J, 2020 Jul;41:2618-2628; Fermo E et al. Front Physiol, 2021 May;12:684569; Xia Y et al. J Clin Lipidol, 2022 Dec;16:40-51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

.;D;D

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D

M_CAP

Benign

0.027

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

.;L;L

PhyloP100

9.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.2

.;.;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0060

.;.;D

Sift4G

Benign

0.069

.;.;T

Polyphen

0.93

.;P;P

Vest4

0.90

MVP

0.36

MPC

0.12

ClinPred

0.30

GERP RS

5.1

Varity_R

0.80

gMVP

0.89

Mutation Taster

=44/56

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over