2-43875495-C-T

Variant names:

• chr2-43875495-C-T
• rs4148222
• NM_022437.3:c.1756+82C>T

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.1756+82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,518,338 control chromosomes in the GnomAD database, including 32,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3979 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28608 hom.)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.157
• Publications: 11 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=-0.9).
• BP6: Variant 2-43875495-C-T is Benign according to our data. Variant chr2-43875495-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285937.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 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.1756+82C>T		intron	N/A	NP_071882.1
	ABCG8	NM_001357321.2		c.1753+82C>T		intron	N/A	NP_001344250.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG8	ENST00000272286.4	TSL:1 MANE Select	c.1756+82C>T		intron	N/A	ENSP00000272286.2
	ABCG8	ENST00000881895.1		c.1771+82C>T		intron	N/A	ENSP00000551954.1
	ABCG8	ENST00000881900.1		c.1768+82C>T		intron	N/A	ENSP00000551959.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32704 AN: 152066 Hom.: 3974 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.188 AC: 256410 AN: 1366150 Hom.: 28608 AF XY: 0.193 AC XY: 130194 AN XY: 674738

African (AFR) AF: 0.277 AC: 8722 AN: 31492

American (AMR) AF: 0.228 AC: 8965 AN: 39328

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2985 AN: 22444

East Asian (EAS) AF: 0.463 AC: 18039 AN: 38936

South Asian (SAS) AF: 0.409 AC: 31002 AN: 75816

European-Finnish (FIN) AF: 0.188 AC: 7637 AN: 40718

Middle Eastern (MID) AF: 0.189 AC: 838 AN: 4444

European-Non Finnish (NFE) AF: 0.158 AC: 167045 AN: 1056194

Other (OTH) AF: 0.197 AC: 11177 AN: 56778

GnomAD4 genome AF: 0.215 AC: 32728 AN: 152188 Hom.: 3979 Cov.: 33 AF XY: 0.221 AC XY: 16466 AN XY: 74418

African (AFR) AF: 0.267 AC: 11083 AN: 41508

American (AMR) AF: 0.227 AC: 3480 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 420 AN: 3472

East Asian (EAS) AF: 0.443 AC: 2289 AN: 5172

South Asian (SAS) AF: 0.425 AC: 2048 AN: 4814

European-Finnish (FIN) AF: 0.176 AC: 1869 AN: 10604

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10899 AN: 67994

Other (OTH) AF: 0.202 AC: 428 AN: 2114

Alfa AF: 0.165 Hom.: 2185

Bravo AF: 0.218

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.36
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4148222; hg19: chr2-44102634;