rs41360247

Variant names:

• chr2-43846517-T-C
• rs41360247
• NM_022437.3:c.322+206T>C

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.322+206T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0652 in 700,082 control chromosomes in the GnomAD database, including 1,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (573 hom., cov: 32)
  • Exomes 𝑓: 0.062 (1186 hom.)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0350
• Publications: 31 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=-0.91).
• BP6: Variant 2-43846517-T-C is Benign according to our data. Variant chr2-43846517-T-C is described in ClinVar as Benign. ClinVar VariationId is 1221022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.322+206T>C		intron_variant	Intron 3 of 12	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.322+206T>C		intron_variant	Intron 3 of 12		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.322+206T>C		intron_variant	Intron 3 of 12	1	NM_022437.3	ENSP00000272286.2
ABCG8	ENST00000643284.1	n.985T>C		non_coding_transcript_exon_variant	Exon 3 of 3
ABCG8	ENST00000644611.1	c.334+206T>C		intron_variant	Intron 3 of 8			ENSP00000495423.1

Frequencies

GnomAD3 genomes AF: 0.0773 AC: 11759 AN: 152104 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0743

Gnomad ASJ AF: 0.0997

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0876

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0621

Gnomad OTH AF: 0.0678

GnomAD4 exome AF: 0.0619 AC: 33907 AN: 547868 Hom.: 1186 Cov.: 7 AF XY: 0.0595 AC XY: 17149 AN XY: 288454

African (AFR) AF: 0.114 AC: 1708 AN: 14962

American (AMR) AF: 0.0972 AC: 2777 AN: 28584

Ashkenazi Jewish (ASJ) AF: 0.0989 AC: 1552 AN: 15692

East Asian (EAS) AF: 0.0102 AC: 291 AN: 28452

South Asian (SAS) AF: 0.0338 AC: 1799 AN: 53246

European-Finnish (FIN) AF: 0.0845 AC: 2304 AN: 27264

Middle Eastern (MID) AF: 0.0587 AC: 128 AN: 2182

European-Non Finnish (NFE) AF: 0.0611 AC: 21315 AN: 348930

Other (OTH) AF: 0.0712 AC: 2033 AN: 28556

GnomAD4 genome AF: 0.0773 AC: 11771 AN: 152214 Hom.: 573 Cov.: 32 AF XY: 0.0770 AC XY: 5731 AN XY: 74426

African (AFR) AF: 0.112 AC: 4670 AN: 41514

American (AMR) AF: 0.0745 AC: 1139 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 346 AN: 3470

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5176

South Asian (SAS) AF: 0.0363 AC: 175 AN: 4826

European-Finnish (FIN) AF: 0.0876 AC: 929 AN: 10600

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0621 AC: 4227 AN: 68018

Other (OTH) AF: 0.0674 AC: 142 AN: 2108

Alfa AF: 0.0674 Hom.: 1077

Bravo AF: 0.0817

Asia WGS AF: 0.0440 AC: 152 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	-0.91
CADD	Benign	1.7
DANN	Benign	0.30
PhyloP100		-0.035
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: rs41360247; hg19: chr2-44073656;