rs137852989

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The ENST00000272286.4(ABCG8):ā€‹c.1974C>Gā€‹(p.Tyr658Ter) 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: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.000017 ( 0 hom. )

Consequence

ABCG8
ENST00000272286.4 stop_gained

Scores

3
2
2

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]

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

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCG8NM_022437.3 linkuse as main transcriptc.1974C>G p.Tyr658Ter stop_gained 13/13 ENST00000272286.4 NP_071882.1
ABCG8NM_001357321.2 linkuse as main transcriptc.1971C>G p.Tyr657Ter stop_gained 13/13 NP_001344250.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCG8ENST00000272286.4 linkuse as main transcriptc.1974C>G p.Tyr658Ter stop_gained 13/131 NM_022437.3 ENSP00000272286 P1Q9H221-1

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152080
Hom.:
0
Cov.:
32
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:
6
AN:
251406
Hom.:
0
AF XY:
0.0000221
AC XY:
3
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:
25
AN:
1461882
Hom.:
0
Cov.:
33
AF XY:
0.0000179
AC XY:
13
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:
12
AN:
152196
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
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.:
0
ExAC
AF:
0.0000165
AC:
2

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
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 19, 2023In 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 submitterclinical testingEurofins Ntd Llc (ga)May 25, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 01, 2024PM2, PM3, PVS1_strong -
Sitosterolemia 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 25, 2022- -
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2000- -
ABCG8-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 01, 2024The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 05, 2024Variant 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
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Benign
0.69
D
MutationTaster
Benign
1.0
A
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.

Other links and lift over

dbSNP: rs137852989; hg19: chr2-44105004; API