NM_022437.3:c.55G>C

Variant names:

Variant summary

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

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,association (★★).

Frequency

Genomes: 𝑓 0.064 ( 383 hom., cov: 32)

Exomes 𝑓: 0.064 ( 3014 hom. )

Consequence

ABCG8
NM_022437.3 missense

Scores

Clinical Significance

Benign/Likely benign; association criteria provided, multiple submitters, no conflicts P:1B:12O:1

Conservation

PhyloP100: 1.10

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 links:

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:

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=0.0018903911).

BP6

Variant 2-43839108-G-C is Benign according to our data. Variant chr2-43839108-G-C is described in ClinVar as [Likely_benign, association]. Clinvar id is 4975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43839108-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.55G>C	p.Asp19His	missense_variant	Exon 1 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG5	XM_047445409.1 link	c.-362C>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13		XP_047301365.1
ABCG8	NM_001357321.2 link	c.55G>C	p.Asp19His	missense_variant	Exon 1 of 13		NP_001344250.1
ABCG5	XM_047445409.1 link	c.-362C>G		5_prime_UTR_variant	Exon 1 of 13		XP_047301365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCG8	ENST00000272286.4 link	c.55G>C	p.Asp19His	missense_variant	Exon 1 of 13	1	NM_022437.3	ENSP00000272286.2	Q9H221-1
ABCG8	ENST00000644611.1 link	c.76-5399G>C		intron_variant	Intron 1 of 8			ENSP00000495423.1	A0A2R8Y6M1
ABCG8	ENST00000643284.1 link	n.521-5399G>C		intron_variant	Intron 1 of 2
ABCG5	ENST00000409962.1 link	n.-243C>G		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0644

AC:

9803

AN:

152164

Hom.:

383

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0669

AC:

10371

AN:

155096

Hom.:

411

AF XY:

0.0638

AC XY:

5223

AN XY:

81892

show subpopulations

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 SAS exome

AF:

0.0337

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.:

AF XY:

0.0626

AC XY:

43195

AN XY:

689968

show subpopulations

Gnomad4 AFR exome

AF:

0.0670

Gnomad4 AMR exome

AF:

0.0939

Gnomad4 ASJ exome

AF:

0.0894

Gnomad4 EAS exome

AF:

0.00932

Gnomad4 SAS exome

AF:

0.0334

Gnomad4 FIN exome

AF:

0.0884

Gnomad4 NFE exome

AF:

0.0652

Gnomad4 OTH exome

AF:

0.0653

GnomAD4 genome

AF:

0.0644

AC:

9810

AN:

152282

Hom.:

383

Cov.:

AF XY:

0.0641

AC XY:

4777

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0650

Gnomad4 AMR

AF:

0.0694

Gnomad4 ASJ

AF:

0.0896

Gnomad4 EAS

AF:

0.0151

Gnomad4 SAS

AF:

0.0356

Gnomad4 FIN

AF:

0.0888

Gnomad4 NFE

AF:

0.0641

Gnomad4 OTH

AF:

0.0562

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:1Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

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

- -

Mar 16, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other: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. -

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) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sitosterolemia

Benign:2

May 28, 2019

Mendelics

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.3

M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

.;N

REVEL

Uncertain

0.36

Sift

Benign

0.045

.;D

Sift4G

Uncertain

0.022

.;D

Polyphen

0.77

P;P

Vest4

0.15

MPC

0.057

ClinPred

0.035

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.11

gMVP

0.50

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