NM_022437.3:c.323-658dupA

Variant names:

• chr2-43850909-C-CA
• rs1164206598
• NM_022437.3:c.323-658dupA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_022437.3(ABCG8):​c.323-658dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 56,930 control chromosomes in the GnomAD database, including 4 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.014 (4 hom., cov: 33)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.906
• Publications: 0 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: Illumina, ClinGen, Orphanet
• sitosterolemia 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0135 (769/56930) while in subpopulation EAS AF = 0.0379 (73/1924). AF 95% confidence interval is 0.0309. There are 4 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	NM_022437.3	MANE Select	c.323-658dupA		intron	N/A	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.323-658dupA		intron	N/A	NP_001344250.1	Q9H221-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.323-675_323-674insA		intron	N/A	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.323-675_323-674insA		intron	N/A	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.323-675_323-674insA		intron	N/A	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 771 AN: 56938 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00845

Gnomad AMI AF: 0.00625

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0238

Gnomad EAS AF: 0.0383

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0196

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

GnomAD4 genome AF: 0.0135 AC: 769 AN: 56930 Hom.: 4 Cov.: 33 AF XY: 0.0145 AC XY: 394 AN XY: 27128

African (AFR) AF: 0.00844 AC: 125 AN: 14816

American (AMR) AF: 0.0263 AC: 140 AN: 5326

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 38 AN: 1594

East Asian (EAS) AF: 0.0379 AC: 73 AN: 1924

South Asian (SAS) AF: 0.0189 AC: 35 AN: 1854

European-Finnish (FIN) AF: 0.0121 AC: 35 AN: 2882

Middle Eastern (MID) AF: 0.0135 AC: 1 AN: 74

European-Non Finnish (NFE) AF: 0.0112 AC: 307 AN: 27424

Other (OTH) AF: 0.0182 AC: 13 AN: 716

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism

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: rs1164206598; hg19: chr2-44078048;