2-43877865-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_022437.3(ABCG8):c.1974C>G(p.Tyr658*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ABCG8
NM_022437.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:2

Conservation

PhyloP100: 2.32

Publications

3 publications found

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 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

ABCG8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0237 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-43877865-C-G is Pathogenic according to our data. Variant chr2-43877865-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4969.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.1974C>G	p.Tyr658*	stop_gained	Exon 13 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.1971C>G	p.Tyr657*	stop_gained	Exon 13 of 13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.1974C>G	p.Tyr658*	stop_gained	Exon 13 of 13	1	NM_022437.3	ENSP00000272286.2		Q9H221-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251406

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1112004

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41536

American (AMR)

AF:

0.000262

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Jul 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PM3, PVS1_strong -

Dec 05, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the homozygous state and with a pathogenic or likely pathogenic variant on the opposite allele (in trans) in patients with sitosterolemia in published literature (PMID: 31893465, 11099417, 11452359); Nonsense variant predicted to result in protein truncation as the last 16 amino acid(s) are lost; This variant is associated with the following publications: (PMID: 31589614, 11099417, 31893465, 11452359, 37647632) -

May 25, 2017

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Tyr658*) in the ABCG8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the ABCG8 protein. This variant is present in population databases (rs137852989, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 11099417). ClinVar contains an entry for this variant (Variation ID: 4969). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sitosterolemia 1

Pathogenic:1Uncertain:1

Dec 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 25, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCG8-related disorder

Pathogenic:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCG8 c.1974C>G variant is predicted to result in premature protein termination (p.Tyr658*). This variant has been reported in an individual with sitosterolemia, who also had a second ABCG8 premature termination variant (Berge et al. 2000. PubMed ID: 11099417). At PreventionGenetics, we have also observed the p.Tyr658* variant in the homozygous state in an individual with sitosterolemia. However, this variant is located just 15 amino acids upstream of the native termination codon, and no other premature termination variants have been reported downstream of this variant. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCG8 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Sitosterolemia

Pathogenic:1

Aug 05, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ABCG8 c.1974C>G (p.Tyr658X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 2.4e-05 in 251406 control chromosomes. c.1974C>G has been reported in the literature in individuals affected with Sitosterolemia (example: Mariano_2019 and Lu_2001). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11452359, 31893465, 35549507). ClinVar contains an entry for this variant (Variation ID: 4969). Based on the evidence outlined above, the variant was classified as pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Feb 05, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y658* variant (also known as c.1974C>G), located in coding exon 13 of the ABCG8 gene, results from a C to G substitution at nucleotide position 1974. This changes the amino acid from a tyrosine to a stop codon within coding exon 13. This alteration occurs at the 3' terminus of theABCG8 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 2.4% of the protein. However, premature stop codons are typically deleterious in nature. This variant has been identified in the homozygous state and/or in conjunction with other ABCG8 variant(s) in individual(s) with features consistent with sitosterolemia (Berge KE et al. Science, 2000 Dec;290:1771-5; Lu K et al. Am J Hum Genet, 2001 Aug;69:278-90; Mariano C et al. Clin Genet, 2020 Mar;97:457-466). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.69

PhyloP100

2.3

Vest4

0.83

GERP RS

4.6

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over