rs6709904

Variant names:

• chr2-43853185-A-G
• rs6709904
• NM_022437.3:c.964+317A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022437.3(ABCG8):​c.964+317A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,170 control chromosomes in the GnomAD database, including 2,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.15 (2306 hom., cov: 33)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.49
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-43853185-A-G is Benign according to our data. Variant chr2-43853185-A-G is described in ClinVar as Benign. ClinVar VariationId is 1250599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.964+317A>G		intron_variant	Intron 6 of 12	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.964+317A>G		intron_variant	Intron 6 of 12		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.964+317A>G		intron_variant	Intron 6 of 12	1	NM_022437.3	ENSP00000272286.2
ABCG8	ENST00000644611.1	c.976+317A>G		intron_variant	Intron 6 of 8			ENSP00000495423.1

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23495 AN: 152052 Hom.: 2291 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.147

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

GnomAD4 genome AF: 0.155 AC: 23548 AN: 152170 Hom.: 2306 Cov.: 33 AF XY: 0.150 AC XY: 11198 AN XY: 74414

African (AFR) AF: 0.275 AC: 11402 AN: 41472

American (AMR) AF: 0.121 AC: 1844 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3472

East Asian (EAS) AF: 0.0220 AC: 114 AN: 5184

South Asian (SAS) AF: 0.130 AC: 625 AN: 4820

European-Finnish (FIN) AF: 0.107 AC: 1134 AN: 10618

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7408 AN: 67990

Other (OTH) AF: 0.145 AC: 307 AN: 2114

Alfa AF: 0.140 Hom.: 3472

Bravo AF: 0.163

Asia WGS AF: 0.101 AC: 350 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.88
CADD	Benign	0.31
DANN	Benign	0.52
PhyloP100		-1.5
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: rs6709904; hg19: chr2-44080324;