chr2-43874688-G-A

Variant names:

• chr2-43874688-G-A
• rs4953028
• NM_022437.3:c.1488+205G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022437.3(ABCG8):​c.1488+205G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 152,042 control chromosomes in the GnomAD database, including 24,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.55 (24464 hom., cov: 32)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.338
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-43874688-G-A is Benign according to our data. Variant chr2-43874688-G-A is described in ClinVar as [Benign]. Clinvar id is 1264649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.1488+205G>A		intron_variant	Intron 10 of 12	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.1485+205G>A		intron_variant	Intron 10 of 12		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.1488+205G>A		intron_variant	Intron 10 of 12	1	NM_022437.3	ENSP00000272286.2

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83619 AN: 151924 Hom.: 24439 Cov.: 32

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.757

Gnomad FIN AF: 0.411

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.573

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

GnomAD4 genome AF: 0.550 AC: 83689 AN: 152042 Hom.: 24464 Cov.: 32 AF XY: 0.554 AC XY: 41185 AN XY: 74310

African (AFR) AF: 0.667 AC: 27643 AN: 41452

American (AMR) AF: 0.582 AC: 8906 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2077 AN: 3472

East Asian (EAS) AF: 0.953 AC: 4923 AN: 5168

South Asian (SAS) AF: 0.757 AC: 3641 AN: 4808

European-Finnish (FIN) AF: 0.411 AC: 4338 AN: 10550

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30335 AN: 67984

Other (OTH) AF: 0.578 AC: 1220 AN: 2112

Alfa AF: 0.487 Hom.: 31472

Bravo AF: 0.570

Asia WGS AF: 0.839 AC: 2916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.29
DANN	Benign	0.23
PhyloP100		-0.34
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: rs4953028; hg19: chr2-44101827;