rs4148217

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022437.3(ABCG8):c.1199C>A(p.Thr400Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,613,206 control chromosomes in the GnomAD database, including 31,756 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T400T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.22 ( 3926 hom., cov: 32)

Exomes 𝑓: 0.19 ( 27830 hom. )

Consequence

ABCG8
NM_022437.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.85

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005831182).

BP6

Variant 2-43872294-C-A is Benign according to our data. Variant chr2-43872294-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 198902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43872294-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.1199C>A	p.Thr400Lys	missense_variant	Exon 8 of 13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.1196C>A	p.Thr399Lys	missense_variant	Exon 8 of 13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.1199C>A	p.Thr400Lys	missense_variant	Exon 8 of 13	1	NM_022437.3	ENSP00000272286.2		Q9H221-1
ABCG8	ENST00000644611.1 link	c.1211C>A	p.Thr404Lys	missense_variant	Exon 8 of 9			ENSP00000495423.1		A0A2R8Y6M1

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33571

AN:

151940

Hom.:

3916

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.275

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.187

Gnomad OTH

AF:

0.229

GnomAD3 exomes

AF:

0.212

AC:

52929

AN:

250160

Hom.:

6204

AF XY:

0.202

AC XY:

27393

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.107

Gnomad SAS exome

AF:

0.148

Gnomad FIN exome

AF:

0.219

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.213

GnomAD4 exome

AF:

0.190

AC:

278140

AN:

1461148

Hom.:

27830

Cov.:

AF XY:

0.188

AC XY:

136853

AN XY:

726846

show subpopulations

Gnomad4 AFR exome

AF:

0.288

Gnomad4 AMR exome

AF:

0.342

Gnomad4 ASJ exome

AF:

0.228

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.217

Gnomad4 NFE exome

AF:

0.184

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.221

AC:

33612

AN:

152058

Hom.:

3926

Cov.:

AF XY:

0.223

AC XY:

16558

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.276

Gnomad4 ASJ

AF:

0.225

Gnomad4 EAS

AF:

0.112

Gnomad4 SAS

AF:

0.150

Gnomad4 FIN

AF:

0.219

Gnomad4 NFE

AF:

0.187

Gnomad4 OTH

AF:

0.229

Alfa

AF:

0.176

Hom.:

1634

Bravo

AF:

0.232

TwinsUK

AF:

0.182

AC:

675

ALSPAC

AF:

0.173

AC:

666

ESP6500AA

AF:

0.273

AC:

1202

ESP6500EA

AF:

0.192

AC:

1647

ExAC

AF:

0.207

AC:

25115

Asia WGS

AF:

0.189

AC:

658

AN:

3478

EpiCase

AF:

0.190

EpiControl

AF:

0.187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 12, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24498041, 25525159, 11893785, 24691589) -

Sitosterolemia 1

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 03, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.32

.;T;T

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.65

T;.;T

MetaRNN

Benign

0.0058

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

.;L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

.;.;N

REVEL

Benign

0.053

Sift

Benign

0.27

.;.;T

Sift4G

Benign

0.34

.;.;T

Polyphen

0.059

.;B;B

Vest4

0.20

MPC

0.017

ClinPred

0.0071

GERP RS

3.9

Varity_R

0.18

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over