2-43839108-G-C

Variant names:

• chr2-43839108-G-C
• rs11887534
• NM_022437.3:c.55G>C

Variant summary

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

The NM_022437.3(ABCG8):​c.55G>C​(p.Asp19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.064 in 1,551,174 control chromosomes in the GnomAD database, including 3,397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,association (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D19E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (383 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3014 hom.)
• Consequence: ABCG8 NM_022437.3 missense
• Clinical Significance: Benign/Likely benign; association criteria provided, multiple submitters, no conflicts P:1 B:13 O:2
• Conservation: PhyloP100: 1.10
• Publications: 196 publications found

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]

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 Gene-Disease associations (from GenCC):

• sitosterolemia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• sitosterolemia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018903911).
• BP6: Variant 2-43839108-G-C is Benign according to our data. Variant chr2-43839108-G-C is described in ClinVar as Benign/Likely_benign|association. ClinVar VariationId is 4975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0659 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	NM_022437.3	MANE Select	c.55G>C	p.Asp19His	missense	Exon 1 of 13	NP_071882.1
	ABCG8	NM_001357321.2		c.55G>C	p.Asp19His	missense	Exon 1 of 13	NP_001344250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.55G>C	p.Asp19His	missense	Exon 1 of 13	ENSP00000272286.2
	ABCG8	ENST00000644611.1		c.76-5399G>C		intron	N/A	ENSP00000495423.1
	ABCG8	ENST00000643284.1		n.521-5399G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 9803 AN: 152164 Hom.: 383 Cov.: 32

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.0151

Gnomad SAS AF: 0.0356

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0573

Gnomad NFE AF: 0.0641

Gnomad OTH AF: 0.0568

GnomAD2 exomes AF: 0.0669 AC: 10371 AN: 155096 AF XY: 0.0638

Gnomad AFR exome AF: 0.0638

Gnomad AMR exome AF: 0.0990

Gnomad ASJ exome AF: 0.0937

Gnomad EAS exome AF: 0.0133

Gnomad FIN exome AF: 0.0942

Gnomad NFE exome AF: 0.0659

Gnomad OTH exome AF: 0.0678

GnomAD4 exome AF: 0.0640 AC: 89470 AN: 1398892 Hom.: 3014 Cov.: 33 AF XY: 0.0626 AC XY: 43195 AN XY: 689968

African (AFR) AF: 0.0670 AC: 2115 AN: 31590

American (AMR) AF: 0.0939 AC: 3352 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 2252 AN: 25178

East Asian (EAS) AF: 0.00932 AC: 333 AN: 35736

South Asian (SAS) AF: 0.0334 AC: 2642 AN: 79220

European-Finnish (FIN) AF: 0.0884 AC: 4341 AN: 49098

Middle Eastern (MID) AF: 0.0604 AC: 343 AN: 5682

European-Non Finnish (NFE) AF: 0.0652 AC: 70306 AN: 1078720

Other (OTH) AF: 0.0653 AC: 3786 AN: 57978

GnomAD4 genome AF: 0.0644 AC: 9810 AN: 152282 Hom.: 383 Cov.: 32 AF XY: 0.0641 AC XY: 4777 AN XY: 74468

African (AFR) AF: 0.0650 AC: 2704 AN: 41572

American (AMR) AF: 0.0694 AC: 1061 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 311 AN: 3470

East Asian (EAS) AF: 0.0151 AC: 78 AN: 5162

South Asian (SAS) AF: 0.0356 AC: 172 AN: 4830

European-Finnish (FIN) AF: 0.0888 AC: 943 AN: 10622

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0641 AC: 4362 AN: 68010

Other (OTH) AF: 0.0562 AC: 119 AN: 2116

Alfa AF: 0.0653 Hom.: 248

Bravo AF: 0.0663

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.0519 AC: 196

ESP6500EA AF: 0.0554 AC: 402

ExAC AF: 0.0307 AC: 1568

Asia WGS AF: 0.0380 AC: 131 AN: 3478

ClinVar

Significance: Benign/Likely benign; association

Submissions summary: Pathogenic:1 Benign:13 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: 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

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

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

not provided Benign:2 Other:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: association

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 19 of the ABCG8 protein (p.Asp19His). This variant is present in population databases (rs11887534, gnomAD 10%), including at least one homozygous and/or hemizygous individual. Population-based case-control studies have shown that this variant is associated with reduced serum phytosterol levels and confers susceptibility to gallstone disease (PMID: 11893785, 17632509, 21039838, 21274884, 22898925). In a large meta-analysis with 4,381 cases and 3,765 controls (PMID: 22898925), individuals carrying this variant had an increased overall risk of gallstone disease (2.07, 95% CI: 1.65-2.60). ClinVar contains an entry for this variant (Variation ID: 4975). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense causes a gain of ABCG8 protein function in vitro, contrary to the loss of ABCG8 protein function associated with sitosterolemia (PMID: 22898925). In summary, this is a common variant that is associated with an increased risk for developing disease. For these reasons, this variant has been classified as an Increased Risk Allele.

Breakthrough Genomics, Breakthrough Genomics

Significance: 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: 29764733, 31327807, 30975109, 30036524, 11893785, 17632509, 20581104, 21039838, 22898925, 20163776, 20592455, 22675952, 20170916)

Sitosterolemia Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gallbladder disease 4 Pathogenic:1

Aug 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sitosterolemia 1 Benign:1

Mar 06, 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.

ABCG8-related disorder Benign:1

Nov 15, 2023

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 2 Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Gallstones Other:1

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Increased Risk Allele and reported on 09-28-2022 by Invitae. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.045	D
Sift4G	Uncertain	0.022	D
Polyphen		0.77	P
Vest4		0.15
MPC		0.057
ClinPred		0.035	T
GERP RS		3.6
PromoterAI		0.094	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.50
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11887534; hg19: chr2-44066247; COSMIC: COSV53211629; COSMIC: COSV53211629;