rs6756629

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022436.3(ABCG5):c.148C>T(p.Arg50Cys) variant causes a missense change. The variant allele was found at a frequency of 0.063 in 1,613,816 control chromosomes in the GnomAD database, including 3,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 425 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3032 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.29

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029157996).

BP6

Variant 2-43837951-G-A is Benign according to our data. Variant chr2-43837951-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 286793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43837951-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG5	NM_022436.3 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	2/13	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG5	ENST00000405322.8 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	2/13	1	NM_022436.3	ENSP00000384513	P1	Q9H222-1

Frequencies

GnomAD3 genomes

AF:

0.0676

AC:

10274

AN:

152086

Hom.:

425

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0795

Gnomad AMI

AF:

0.0407

Gnomad AMR

AF:

0.0706

Gnomad ASJ

AF:

0.0888

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0359

Gnomad FIN

AF:

0.0877

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0623

Gnomad OTH

AF:

0.0583

GnomAD3 exomes

AF:

0.0667

AC:

16775

AN:

251368

Hom.:

635

AF XY:

0.0639

AC XY:

8683

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.0782

Gnomad AMR exome

AF:

0.104

Gnomad ASJ exome

AF:

0.0929

Gnomad EAS exome

AF:

0.0138

Gnomad SAS exome

AF:

0.0341

Gnomad FIN exome

AF:

0.0909

Gnomad NFE exome

AF:

0.0640

Gnomad OTH exome

AF:

0.0688

GnomAD4 exome

AF:

0.0625

AC:

91412

AN:

1461612

Hom.:

3032

Cov.:

AF XY:

0.0611

AC XY:

44459

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.0823

Gnomad4 AMR exome

AF:

0.0988

Gnomad4 ASJ exome

AF:

0.0876

Gnomad4 EAS exome

AF:

0.00962

Gnomad4 SAS exome

AF:

0.0334

Gnomad4 FIN exome

AF:

0.0865

Gnomad4 NFE exome

AF:

0.0628

Gnomad4 OTH exome

AF:

0.0652

GnomAD4 genome

AF:

0.0676

AC:

10286

AN:

152204

Hom.:

425

Cov.:

AF XY:

0.0672

AC XY:

4998

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0795

Gnomad4 AMR

AF:

0.0708

Gnomad4 ASJ

AF:

0.0888

Gnomad4 EAS

AF:

0.0149

Gnomad4 SAS

AF:

0.0359

Gnomad4 FIN

AF:

0.0877

Gnomad4 NFE

AF:

0.0623

Gnomad4 OTH

AF:

0.0577

Alfa

AF:

0.0638

Hom.:

806

Bravo

AF:

0.0700

TwinsUK

AF:

0.0663

AC:

246

ALSPAC

AF:

0.0535

AC:

206

ESP6500AA

AF:

0.0724

AC:

319

ESP6500EA

AF:

0.0637

AC:

548

ExAC

AF:

0.0643

AC:

7806

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

EpiCase

AF:

0.0666

EpiControl

AF:

0.0659

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 24633158, 22898925, 27291889, 28008009, 29353225, 19060911) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sitosterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

ABCG5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Sitosterolemia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D

Eigen

Benign

0.14

Eigen_PC

Benign

-0.0074

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-2.7

D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.011

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.14

MPC

0.098

ClinPred

0.025

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.13

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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