rs4148214

Variant names:

• chr2-43851865-T-C
• rs4148214
• NM_022437.3:c.561+43T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-43851865-T-C
• chr2-43851865-T-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.561+43T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 1,601,100 control chromosomes in the GnomAD database, including 277,046 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28616 hom., cov: 33)
  • Exomes 𝑓: 0.58 (248430 hom.)
• Consequence: ABCG8 NM_022437.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.106
• Publications: 15 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=-0.87).
• BP6: Variant 2-43851865-T-C is Benign according to our data. Variant chr2-43851865-T-C is described in ClinVar as Benign. ClinVar VariationId is 1188927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3	c.561+43T>C		intron_variant	Intron 4 of 12	ENST00000272286.4	NP_071882.1
ABCG8	NM_001357321.2	c.561+43T>C		intron_variant	Intron 4 of 12		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4	c.561+43T>C		intron_variant	Intron 4 of 12	1	NM_022437.3	ENSP00000272286.2
ABCG8	ENST00000644611.1	c.573+43T>C		intron_variant	Intron 4 of 8			ENSP00000495423.1

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92506 AN: 151962 Hom.: 28581 Cov.: 33

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.865

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.577

GnomAD2 exomes AF: 0.614 AC: 151447 AN: 246740 AF XY: 0.616

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.557

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.880

Gnomad FIN exome AF: 0.597

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.582 AC: 843229 AN: 1449020 Hom.: 248430 Cov.: 30 AF XY: 0.585 AC XY: 422008 AN XY: 721546

African (AFR) AF: 0.674 AC: 22416 AN: 33272

American (AMR) AF: 0.556 AC: 24848 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15809 AN: 26080

East Asian (EAS) AF: 0.835 AC: 33111 AN: 39642

South Asian (SAS) AF: 0.708 AC: 60914 AN: 86024

European-Finnish (FIN) AF: 0.597 AC: 30182 AN: 50598

Middle Eastern (MID) AF: 0.545 AC: 3126 AN: 5736

European-Non Finnish (NFE) AF: 0.560 AC: 617435 AN: 1102926

Other (OTH) AF: 0.589 AC: 35388 AN: 60042

GnomAD4 genome AF: 0.609 AC: 92587 AN: 152080 Hom.: 28616 Cov.: 33 AF XY: 0.611 AC XY: 45400 AN XY: 74314

African (AFR) AF: 0.677 AC: 28064 AN: 41476

American (AMR) AF: 0.547 AC: 8362 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2098 AN: 3472

East Asian (EAS) AF: 0.864 AC: 4479 AN: 5182

South Asian (SAS) AF: 0.716 AC: 3451 AN: 4820

European-Finnish (FIN) AF: 0.600 AC: 6340 AN: 10564

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37925 AN: 67958

Other (OTH) AF: 0.580 AC: 1225 AN: 2112

Alfa AF: 0.590 Hom.: 25761

Bravo AF: 0.607

Asia WGS AF: 0.750 AC: 2608 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Sitosterolemia 1 Benign:1

Jul 14, 2021

Genome-Nilou Lab

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	-0.87
CADD	Benign	6.5
DANN	Benign	0.76
PhyloP100		-0.11
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: rs4148214; hg19: chr2-44079004;