rs4148211

Positions:

chr2-43844604-A-G

Variant summary

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

The NM_022437.3(ABCG8):c.161A>G(p.Tyr54Cys) variant causes a missense change. The variant allele was found at a frequency of 0.402 in 1,609,778 control chromosomes in the GnomAD database, including 138,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.36 ( 11209 hom., cov: 32)

Exomes 𝑓: 0.41 ( 127232 hom. )

Consequence

ABCG8
NM_022437.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.21

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=1.0526757E-6).

BP6

Variant 2-43844604-A-G is Benign according to our data. Variant chr2-43844604-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 288558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43844604-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.837 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.161A>G	p.Tyr54Cys	missense_variant	2/13	ENST00000272286.4	NP_071882.1	Q9H221-1
ABCG8	NM_001357321.2 link	c.161A>G	p.Tyr54Cys	missense_variant	2/13		NP_001344250.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCG8	ENST00000272286.4 link	c.161A>G	p.Tyr54Cys	missense_variant	2/13	1	NM_022437.3	ENSP00000272286.2	Q9H221-1
ABCG8	ENST00000644611.1 link	c.173A>G	p.Tyr58Cys	missense_variant	2/9			ENSP00000495423.1	A0A2R8Y6M1
ABCG8	ENST00000643284.1 link	n.618A>G		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes

AF:

0.359

AC:

54458

AN:

151858

Hom.:

11196

Cov.:

show subpopulations

Gnomad AFR

AF:

0.196

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.370

Gnomad ASJ

AF:

0.373

Gnomad EAS

AF:

0.858

Gnomad SAS

AF:

0.532

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.390

Gnomad OTH

AF:

0.348

GnomAD3 exomes

AF:

0.429

AC:

107424

AN:

250470

Hom.:

25606

AF XY:

0.434

AC XY:

58766

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.187

Gnomad AMR exome

AF:

0.391

Gnomad ASJ exome

AF:

0.368

Gnomad EAS exome

AF:

0.871

Gnomad SAS exome

AF:

0.512

Gnomad FIN exome

AF:

0.449

Gnomad NFE exome

AF:

0.384

Gnomad OTH exome

AF:

0.401

GnomAD4 exome

AF:

0.407

AC:

593182

AN:

1457802

Hom.:

127232

Cov.:

AF XY:

0.410

AC XY:

297397

AN XY:

725404

show subpopulations

Gnomad4 AFR exome

AF:

0.182

Gnomad4 AMR exome

AF:

0.389

Gnomad4 ASJ exome

AF:

0.373

Gnomad4 EAS exome

AF:

0.850

Gnomad4 SAS exome

AF:

0.508

Gnomad4 FIN exome

AF:

0.446

Gnomad4 NFE exome

AF:

0.391

Gnomad4 OTH exome

AF:

0.398

GnomAD4 genome

AF:

0.358

AC:

54472

AN:

151976

Hom.:

11209

Cov.:

AF XY:

0.368

AC XY:

27316

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.196

Gnomad4 AMR

AF:

0.370

Gnomad4 ASJ

AF:

0.373

Gnomad4 EAS

AF:

0.858

Gnomad4 SAS

AF:

0.532

Gnomad4 FIN

AF:

0.454

Gnomad4 NFE

AF:

0.390

Gnomad4 OTH

AF:

0.354

Alfa

AF:

0.391

Hom.:

28353

Bravo

AF:

0.343

TwinsUK

AF:

0.376

AC:

1394

ALSPAC

AF:

0.396

AC:

1527

ESP6500AA

AF:

0.195

AC:

860

ESP6500EA

AF:

0.385

AC:

3313

ExAC

AF:

0.425

AC:

51648

Asia WGS

AF:

0.602

AC:

2095

AN:

3478

EpiCase

AF:

0.375

EpiControl

AF:

0.375

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 17827468, 24498041, 20854103, 20170916) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Sitosterolemia 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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

0.14

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;D;D

Eigen

Benign

-0.016

Eigen_PC

Benign

0.11

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

T;.;T

MetaRNN

Benign

0.0000011

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

.;L;L

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.2

.;.;D

REVEL

Uncertain

0.32

Sift

Benign

0.043

.;.;D

Sift4G

Uncertain

0.041

.;.;D

Polyphen

0.21

.;B;B

Vest4

0.18

MPC

0.024

ClinPred

0.033

GERP RS

4.1

Varity_R

0.29

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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