chr2-43846861-G-A

Variant names:

• chr2-43846861-G-A
• rs4953023
• NM_022437.3:c.322+550G>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.322+550G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0675 in 187,758 control chromosomes in the GnomAD database, including 498 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 0.068 (421 hom., cov: 32)
  • Exomes 𝑓: 0.063 (77 hom.)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 29 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0798 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.322+550G>A		intron	N/A	NP_071882.1
	ABCG8	NM_001357321.2		c.322+550G>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.322+550G>A		intron	N/A	ENSP00000272286.2
	ABCG8	ENST00000643284.1		n.1329G>A		non_coding_transcript_exon	Exon 3 of 3
	ABCG8	ENST00000644611.1		c.334+550G>A		intron	N/A	ENSP00000495423.1

Frequencies

GnomAD3 genomes AF: 0.0685 AC: 10413 AN: 152052 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.0822

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.0355

Gnomad FIN AF: 0.0874

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.0608

GnomAD4 exome AF: 0.0633 AC: 2252 AN: 35588 Hom.: 77 Cov.: 0 AF XY: 0.0615 AC XY: 1109 AN XY: 18030

African (AFR) AF: 0.0782 AC: 71 AN: 908

American (AMR) AF: 0.104 AC: 351 AN: 3384

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 58 AN: 670

East Asian (EAS) AF: 0.0109 AC: 26 AN: 2382

South Asian (SAS) AF: 0.0341 AC: 134 AN: 3930

European-Finnish (FIN) AF: 0.0853 AC: 132 AN: 1548

Middle Eastern (MID) AF: 0.0600 AC: 6 AN: 100

European-Non Finnish (NFE) AF: 0.0652 AC: 1352 AN: 20752

Other (OTH) AF: 0.0637 AC: 122 AN: 1914

GnomAD4 genome AF: 0.0685 AC: 10423 AN: 152170 Hom.: 421 Cov.: 32 AF XY: 0.0680 AC XY: 5061 AN XY: 74392

African (AFR) AF: 0.0821 AC: 3408 AN: 41488

American (AMR) AF: 0.0716 AC: 1095 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 347 AN: 3472

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5186

South Asian (SAS) AF: 0.0355 AC: 171 AN: 4816

European-Finnish (FIN) AF: 0.0874 AC: 926 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0619 AC: 4212 AN: 68012

Other (OTH) AF: 0.0602 AC: 127 AN: 2110

Alfa AF: 0.0664 Hom.: 1128

Bravo AF: 0.0715

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.62
PhyloP100		1.6
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: rs4953023; hg19: chr2-44074000;