chr2-43869631-T-A

Variant names:

• chr2-43869631-T-A
• rs4952688
• NM_022437.3:c.965-2345T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022437.3(ABCG8):​c.965-2345T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 151,862 control chromosomes in the GnomAD database, including 50,560 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.81 (50560 hom., cov: 31)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.95
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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.965-2345T>A		intron	N/A	NP_071882.1
	ABCG8	NM_001357321.2		c.965-2345T>A		intron	N/A	NP_001344250.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.965-2345T>A		intron	N/A	ENSP00000272286.2
	ABCG8	ENST00000644611.1		c.977-2345T>A		intron	N/A	ENSP00000495423.1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123155 AN: 151744 Hom.: 50506 Cov.: 31

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.691

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.861

Gnomad FIN AF: 0.813

Gnomad MID AF: 0.784

Gnomad NFE AF: 0.731

Gnomad OTH AF: 0.792

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.812 AC: 123264 AN: 151862 Hom.: 50560 Cov.: 31 AF XY: 0.817 AC XY: 60594 AN XY: 74206

African (AFR) AF: 0.922 AC: 38286 AN: 41522

American (AMR) AF: 0.803 AC: 12271 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2828 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5113 AN: 5142

South Asian (SAS) AF: 0.861 AC: 4130 AN: 4798

European-Finnish (FIN) AF: 0.813 AC: 8590 AN: 10566

Middle Eastern (MID) AF: 0.785 AC: 226 AN: 288

European-Non Finnish (NFE) AF: 0.731 AC: 49518 AN: 67784

Other (OTH) AF: 0.794 AC: 1675 AN: 2110

Alfa AF: 0.763 Hom.: 5235

Bravo AF: 0.817

Asia WGS AF: 0.932 AC: 3237 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.067
DANN	Benign	0.13
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4952688; hg19: chr2-44096770;