rs137852989

Positions:

chr2-43877865-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 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:5U:2

Conservation

PhyloP100: 2.32

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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 0 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 id is 4969.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG8	NM_022437.3 linkuse as main transcript	c.1974C>G	p.Tyr658*	stop_gained	13/13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 linkuse as main transcript	c.1971C>G	p.Tyr657*	stop_gained	13/13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 linkuse as main transcript	c.1974C>G	p.Tyr658*	stop_gained	13/13	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

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251406

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135890

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 01, 2024	PM2, PM3, PVS1_strong -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2023	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. ClinVar contains an entry for this variant (Variation ID: 4969). This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 11099417). This variant is present in population databases (rs137852989, gnomAD 0.02%). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2017	- -

Sitosterolemia 1

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 25, 2022	- -

ABCG8-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 05, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Benign

0.69

Vest4

0.83

GERP RS

4.6

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

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