rs9282575

chr2-43852467-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0900

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]

ACMG classification

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	c.675G>A	p.Val225=	synonymous_variant	5/13	ENST00000272286.4
ABCG8	NM_001357321.2	c.675G>A	p.Val225=	synonymous_variant	5/13

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7280 AN: 152134 Hom.: 218 Cov.: 33

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

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.: 34 AF XY: 0.0520 AC XY: 37810 AN XY: 726782

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.: 33 AF XY: 0.0453 AC XY: 3369 AN XY: 74438

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sitosterolemia 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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

Other links and lift over

dbSNP: rs9282575; hg19: chr2-44079606;