2-43839035-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022437.3(ABCG8):c.-19T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,549,390 control chromosomes in the GnomAD database, including 104,532 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11545 hom., cov: 32)

Exomes 𝑓: 0.35 ( 92987 hom. )

Consequence

ABCG8
NM_022437.3 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.65

Publications

24 publications found

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:

ABCG5 (HGNC:13886): (ATP binding cassette subfamily G member 5) 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 as a half-transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue-specific manner in the liver, colon, and intestine. This gene is tandemly arrayed on chromosome 2, in a head-to-head orientation with family member ABCG8. Mutations in this gene may contribute to sterol accumulation and atheroschlerosis, and have been observed in patients with sitosterolemia. [provided by RefSeq, Jul 2008]

ABCG5 Gene-Disease associations (from GenCC):

sitosterolemia
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
sitosterolemia 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
sitosterolemia 2
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ABCG5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 2-43839035-T-G is Benign according to our data. Variant chr2-43839035-T-G is described in ClinVar as Benign. ClinVar VariationId is 193450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG8	NM_022437.3 link	c.-19T>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000272286.4	NP_071882.1
ABCG5	NM_022436.3 link	c.-356A>C		upstream_gene_variant		ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG8	ENST00000272286.4 link	c.-19T>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_022437.3	ENSP00000272286.2
ABCG5	ENST00000405322.8 link	c.-356A>C		upstream_gene_variant		1	NM_022436.3	ENSP00000384513.2

Frequencies

GnomAD3 genomes

AF:

0.375

AC:

56881

AN:

151856

Hom.:

11520

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.187

Gnomad AMR

AF:

0.363

Gnomad ASJ

AF:

0.245

Gnomad EAS

AF:

0.845

Gnomad SAS

AF:

0.524

Gnomad FIN

AF:

0.372

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.323

Gnomad OTH

AF:

0.352

GnomAD2 exomes

AF:

0.398

AC:

61687

AN:

154852

AF XY:

0.403

show subpopulations

Gnomad AFR exome

AF:

0.400

Gnomad AMR exome

AF:

0.374

Gnomad ASJ exome

AF:

0.230

Gnomad EAS exome

AF:

0.852

Gnomad FIN exome

AF:

0.369

Gnomad NFE exome

AF:

0.318

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.351

AC:

489991

AN:

1397414

Hom.:

92987

Cov.:

AF XY:

0.355

AC XY:

244563

AN XY:

689280

show subpopulations

African (AFR)

AF:

0.396

AC:

12490

AN:

31548

American (AMR)

AF:

0.372

AC:

13261

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

6008

AN:

25166

East Asian (EAS)

AF:

0.852

AC:

30439

AN:

35726

South Asian (SAS)

AF:

0.501

AC:

39633

AN:

79134

European-Finnish (FIN)

AF:

0.369

AC:

18057

AN:

48920

Middle Eastern (MID)

AF:

0.261

AC:

1414

AN:

5416

European-Non Finnish (NFE)

AF:

0.323

AC:

348145

AN:

1077914

Other (OTH)

AF:

0.355

AC:

20544

AN:

57896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

14603

29206

43809

58412

73015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11684

23368

35052

46736

58420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.375

AC:

56943

AN:

151976

Hom.:

11545

Cov.:

AF XY:

0.383

AC XY:

28420

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.405

AC:

16800

AN:

41440

American (AMR)

AF:

0.363

AC:

5545

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.245

AC:

849

AN:

3472

East Asian (EAS)

AF:

0.845

AC:

4357

AN:

5154

South Asian (SAS)

AF:

0.524

AC:

2518

AN:

4808

European-Finnish (FIN)

AF:

0.372

AC:

3937

AN:

10576

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.323

AC:

21952

AN:

67928

Other (OTH)

AF:

0.358

AC:

756

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1800

3600

5400

7200

9000

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.247

Hom.:

864

Bravo

AF:

0.371

Asia WGS

AF:

0.606

AC:

2107

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 16, 2015

Eurofins Ntd Llc (ga)

Significance: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

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

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sitosterolemia 1

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 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.

not provided

Benign:2

Oct 14, 2020

GeneDx

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

Sitosterolemia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

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

-0.89

CADD

Benign

0.77

(source)

DANN

Benign

0.68

PhyloP100

-1.6

PromoterAI

0.0080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over