2-43832056-G-C

Position:

chr2-43832056-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_022436.3(ABCG5):c.293C>G(p.Ala98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,581,976 control chromosomes in the GnomAD database, including 13 homozygotes. 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. A98C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 12 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 9.21

Variant links:

Genes affected

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) 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 as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG5 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028946191).

BP6

Variant 2-43832056-G-C is Benign according to our data. Variant chr2-43832056-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289815.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=3, Likely_benign=2}. Variant chr2-43832056-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.002 (304/152280) while in subpopulation AMR AF= 0.00418 (64/15302). AF 95% confidence interval is 0.00336. There are 1 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG5	NM_022436.3 linkuse as main transcript	c.293C>G	p.Ala98Gly	missense_variant	3/13	ENST00000405322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG5	ENST00000405322.8 linkuse as main transcript	c.293C>G	p.Ala98Gly	missense_variant	3/13	1	NM_022436.3	P1	Q9H222-1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

304

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00237

AC:

463

AN:

194998

Hom.:

AF XY:

0.00254

AC XY:

267

AN XY:

105104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.00220

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00214

AC:

3061

AN:

1429696

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

1542

AN XY:

707604

show subpopulations

Gnomad4 AFR exome

AF:

0.000334

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00380

Gnomad4 FIN exome

AF:

0.00128

Gnomad4 NFE exome

AF:

0.00190

Gnomad4 OTH exome

AF:

0.00274

GnomAD4 genome

AF:

0.00200

AC:

304

AN:

152280

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00418

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00234

AC:

ExAC

AF:

0.00169

AC:

202

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 10, 2017	- -

Sitosterolemia 1

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ABCG5: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2022	See Variant Classification Assertion Criteria. -

ABCG5-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The ABCG5 c.293C>G variant is predicted to result in the amino acid substitution p.Ala98Gly. This variant was reported in the heterozygous state in three Argentinian individuals with hypercholesterolemia (Corral et al. 2018. PubMed ID: 30270055). This variant was also identified in the heterozygous state in two unrelated patients with moderate thrombocytopenia and bleeding scores of 0 and 4 (Ali et al. 2016. PubMed ID: 27291889). A blood smear from the patient with the bleeding score of 0 revealed stomatocytes which, along with macrothrombocytopenia, are a feature of sitosterolemia, a disorder associated with recessive inheritance of variants in the ABCG5 gene. A second pathogenic variant was not identified in either patient in the Ali et al. report. This variant is reported in 1.0% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, and one homozygous individual has been documented. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hyperuricemic nephropathy, familial juvenile type 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 05, 2021

- -

Sitosterolemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

.;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.029

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

D;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.018

D;.

Polyphen

0.98

D;D

Vest4

0.72

MVP

0.92

MPC

0.34

ClinPred

0.065

GERP RS

5.4

Varity_R

0.79

gMVP

0.74

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over