rs9282575

Variant names:

• chr2-43852467-G-A
• rs9282575
• NM_022437.3:c.675G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-43852467-G-A
• chr2-43852467-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_022437.3(ABCG8):​c.675G>A​(p.Val225Val) 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:8
• Conservation: PhyloP100: 0.0900
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 336072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	NM_022437.3	MANE Select	c.675G>A	p.Val225Val	synonymous	Exon 5 of 13	NP_071882.1
	ABCG8	NM_001357321.2		c.675G>A	p.Val225Val	synonymous	Exon 5 of 13	NP_001344250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.675G>A	p.Val225Val	synonymous	Exon 5 of 13	ENSP00000272286.2
	ABCG8	ENST00000644611.1		c.687G>A	p.Val229Val	synonymous	Exon 5 of 9	ENSP00000495423.1

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

GnomAD2 exomes AF: 0.0483 AC: 12096 AN: 250588 AF XY: 0.0521

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 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

African (AFR) AF: 0.0646 AC: 2162 AN: 33448

American (AMR) AF: 0.0287 AC: 1282 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 1974 AN: 26130

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.105 AC: 9065 AN: 86208

European-Finnish (FIN) AF: 0.0184 AC: 983 AN: 53370

Middle Eastern (MID) AF: 0.122 AC: 639 AN: 5254

European-Non Finnish (NFE) AF: 0.0482 AC: 53563 AN: 1111856

Other (OTH) AF: 0.0537 AC: 3237 AN: 60326

GnomAD4 genome AF: 0.0478 AC: 7278 AN: 152252 Hom.: 218 Cov.: 33 AF XY: 0.0453 AC XY: 3369 AN XY: 74438

African (AFR) AF: 0.0589 AC: 2446 AN: 41530

American (AMR) AF: 0.0373 AC: 571 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 247 AN: 3472

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.0935 AC: 451 AN: 4822

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10630

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3172 AN: 68006

Other (OTH) AF: 0.0586 AC: 124 AN: 2116

Alfa AF: 0.0486 Hom.: 139

Bravo AF: 0.0486

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.0523

EpiControl AF: 0.0589

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Sitosterolemia 1 (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.3
DANN	Benign	0.83
PhyloP100		0.090
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9282575; hg19: chr2-44079606;