rs9282575

Positions:

chr2-43852467-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022437.3(ABCG8):c.675G>A(p.Val225=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,613,262 control chromosomes in the GnomAD database, including 2,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 218 hom., cov: 33)

Exomes 𝑓: 0.050 ( 2215 hom. )

Consequence

ABCG8
NM_022437.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0900

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 2-43852467-G-A is Benign according to our data. Variant chr2-43852467-G-A is described in ClinVar as [Benign]. Clinvar id is 336072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43852467-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0864 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCG8	NM_022437.3 linkuse as main transcript	c.675G>A	p.Val225=	synonymous_variant	5/13	ENST00000272286.4
ABCG8	NM_001357321.2 linkuse as main transcript	c.675G>A	p.Val225=	synonymous_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG8	ENST00000272286.4 linkuse as main transcript	c.675G>A	p.Val225=	synonymous_variant	5/13	1	NM_022437.3	P1	Q9H221-1
ABCG8	ENST00000644611.1 linkuse as main transcript	c.687G>A	p.Val229=	synonymous_variant	5/9

Frequencies

GnomAD3 genomes

AF:

0.0479

AC:

7280

AN:

152134

Hom.:

218

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0590

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0374

Gnomad ASJ

AF:

0.0711

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0928

Gnomad FIN

AF:

0.0190

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0467

Gnomad OTH

AF:

0.0597

GnomAD3 exomes

AF:

0.0483

AC:

12096

AN:

250588

Hom.:

401

AF XY:

0.0521

AC XY:

7062

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.0603

Gnomad AMR exome

AF:

0.0263

Gnomad ASJ exome

AF:

0.0762

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.102

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.0495

Gnomad OTH exome

AF:

0.0560

GnomAD4 exome

AF:

0.0499

AC:

72910

AN:

1461010

Hom.:

2215

Cov.:

AF XY:

0.0520

AC XY:

37810

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.0646

Gnomad4 AMR exome

AF:

0.0287

Gnomad4 ASJ exome

AF:

0.0755

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.0184

Gnomad4 NFE exome

AF:

0.0482

Gnomad4 OTH exome

AF:

0.0537

GnomAD4 genome

AF:

0.0478

AC:

7278

AN:

152252

Hom.:

218

Cov.:

AF XY:

0.0453

AC XY:

3369

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0589

Gnomad4 AMR

AF:

0.0373

Gnomad4 ASJ

AF:

0.0711

Gnomad4 EAS

AF:

0.000581

Gnomad4 SAS

AF:

0.0935

Gnomad4 FIN

AF:

0.0190

Gnomad4 NFE

AF:

0.0466

Gnomad4 OTH

AF:

0.0586

Alfa

AF:

0.0488

Hom.:

125

Bravo

AF:

0.0486

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

EpiCase

AF:

0.0523

EpiControl

AF:

0.0589

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Sitosterolemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 10, 2023

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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

BayesDel_noAF

Benign

-0.47

CADD

Benign

6.3

DANN

Benign

0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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