2-43846742-T-C

Variant names:

• chr2-43846742-T-C
• rs6544713
• NM_022437.3:c.322+431T>C

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.322+431T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 269,698 control chromosomes in the GnomAD database, including 75,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (43928 hom., cov: 31)
  • Exomes 𝑓: 0.73 (31501 hom.)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.186
• Publications: 138 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-43846742-T-C is Benign according to our data. Variant chr2-43846742-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164919.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	NM_022437.3	MANE Select	c.322+431T>C		intron	N/A	NP_071882.1	Q9H221-1
	ABCG8	NM_001357321.2		c.322+431T>C		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.322+431T>C		intron	N/A	ENSP00000272286.2	Q9H221-1
	ABCG8	ENST00000881895.1		c.322+431T>C		intron	N/A	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.322+431T>C		intron	N/A	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114824 AN: 152052 Hom.: 43866 Cov.: 31

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.791

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.725

GnomAD4 exome AF: 0.728 AC: 85614 AN: 117528 Hom.: 31501 Cov.: 0 AF XY: 0.730 AC XY: 44937 AN XY: 61584

African (AFR) AF: 0.841 AC: 3408 AN: 4054

American (AMR) AF: 0.792 AC: 4255 AN: 5372

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2147 AN: 2982

East Asian (EAS) AF: 0.998 AC: 5807 AN: 5820

South Asian (SAS) AF: 0.737 AC: 13221 AN: 17938

European-Finnish (FIN) AF: 0.782 AC: 4524 AN: 5784

Middle Eastern (MID) AF: 0.589 AC: 264 AN: 448

European-Non Finnish (NFE) AF: 0.689 AC: 47631 AN: 69112

Other (OTH) AF: 0.724 AC: 4357 AN: 6018

GnomAD4 genome AF: 0.755 AC: 114941 AN: 152170 Hom.: 43928 Cov.: 31 AF XY: 0.763 AC XY: 56787 AN XY: 74406

African (AFR) AF: 0.838 AC: 34771 AN: 41514

American (AMR) AF: 0.763 AC: 11657 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2531 AN: 3470

East Asian (EAS) AF: 0.994 AC: 5150 AN: 5180

South Asian (SAS) AF: 0.771 AC: 3713 AN: 4816

European-Finnish (FIN) AF: 0.791 AC: 8389 AN: 10600

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.683 AC: 46415 AN: 67996

Other (OTH) AF: 0.728 AC: 1533 AN: 2106

Alfa AF: 0.709 Hom.: 142364

Bravo AF: 0.759

Asia WGS AF: 0.887 AC: 3083 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.78
PhyloP100		-0.19
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: rs6544713; hg19: chr2-44073881;