rs6756629

Variant names:

• chr2-43837951-G-A
• rs6756629
• NM_022436.3:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-43837951-G-A
• chr2-43837951-G-C
• chr2-43837951-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.068 (425 hom., cov: 32)
  • Exomes 𝑓: 0.063 (3032 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 5.29
• Publications: 111 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 286793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ABCG5	NM_022436.3	c.148C>T	p.Arg50Cys	missense_variant	Exon 2 of 13	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG5	ENST00000405322.8	c.148C>T	p.Arg50Cys	missense_variant	Exon 2 of 13	1	NM_022436.3	ENSP00000384513.2

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10274 AN: 152086 Hom.: 425 Cov.: 32

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

GnomAD2 exomes AF: 0.0667 AC: 16775 AN: 251368 AF XY: 0.0639

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 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.: 31 AF XY: 0.0611 AC XY: 44459 AN XY: 727118

African (AFR) AF: 0.0823 AC: 2756 AN: 33478

American (AMR) AF: 0.0988 AC: 4418 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0876 AC: 2288 AN: 26128

East Asian (EAS) AF: 0.00962 AC: 382 AN: 39698

South Asian (SAS) AF: 0.0334 AC: 2881 AN: 86250

European-Finnish (FIN) AF: 0.0865 AC: 4617 AN: 53374

Middle Eastern (MID) AF: 0.0604 AC: 348 AN: 5766

European-Non Finnish (NFE) AF: 0.0628 AC: 69786 AN: 1111836

Other (OTH) AF: 0.0652 AC: 3936 AN: 60366

GnomAD4 genome AF: 0.0676 AC: 10286 AN: 152204 Hom.: 425 Cov.: 32 AF XY: 0.0672 AC XY: 4998 AN XY: 74428

African (AFR) AF: 0.0795 AC: 3302 AN: 41540

American (AMR) AF: 0.0708 AC: 1082 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0888 AC: 308 AN: 3468

East Asian (EAS) AF: 0.0149 AC: 77 AN: 5182

South Asian (SAS) AF: 0.0359 AC: 173 AN: 4820

European-Finnish (FIN) AF: 0.0877 AC: 929 AN: 10598

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0623 AC: 4239 AN: 67988

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0661 Hom.: 1242

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24633158, 22898925, 27291889, 28008009, 29353225, 19060911) -

Sitosterolemia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCG5-related disorder Benign:1

Jan 31, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 03, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D
Eigen	Benign	0.14
Eigen_PC	Benign	-0.0074
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	.;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.8	L;L
PhyloP100		5.3
PrimateAI	Benign	0.20	T
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	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.70
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6756629; hg19: chr2-44065090; COSMIC: COSV53211625; COSMIC: COSV53211625;