2-43824071-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4

The NM_022436.3(ABCG5):c.1166G>A(p.Arg389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R389C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 7.50

Publications

33 publications found

Variant links:

Genes affected

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 links:

DYNC2LI1 (HGNC:24595): (dynein cytoplasmic 2 light intermediate chain 1) This gene encodes a protein that is a component of the dynein-2 microtubule motor protein complex that plays a role in the retrograde transport of cargo in primary cilia via the intraflagellar transport system. This gene is ubiquitously expressed and its protein, which localizes to the axoneme and Golgi apparatus, interacts directly with the cytoplasmic dynein 2 heavy chain 1 protein to form part of the multi-protein dynein-2 complex. Mutations in this gene produce defects in the dynein-2 complex which result in several types of ciliopathy including short-rib thoracic dysplasia 15 with polydactyly (SRTD15). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

DYNC2LI1 Gene-Disease associations (from GenCC):

short-rib thoracic dysplasia 15 with polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Ellis-van Creveld syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Jeune syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DYNC2LI1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP5

Variant 2-43824071-C-T is Pathogenic according to our data. Variant chr2-43824071-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18254992). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG5	NM_022436.3 link	c.1166G>A	p.Arg389His	missense_variant	Exon 9 of 13	ENST00000405322.8	NP_071881.1	Q9H222-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCG5	ENST00000405322.8 link	c.1166G>A	p.Arg389His	missense_variant	Exon 9 of 13	1	NM_022436.3	ENSP00000384513.2	Q9H222-1
ABCG5	ENST00000486512.5 link	n.1687G>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
ABCG5	ENST00000409962.1 link	n.1449G>A		non_coding_transcript_exon_variant	Exon 5 of 9	2
ABCG5	ENST00000644754.1 link	n.1550G>A		non_coding_transcript_exon_variant	Exon 6 of 10

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000151

AC:

AN:

251474

AF XY:

0.000132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00154

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1112008

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00212

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sitosterolemia 2

Pathogenic:3

Jun 30, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1+PP3+PM3_VeryStrong+PM2_Supporting -

not provided

Pathogenic:2

Feb 08, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PS4, PM3 -

ABCG5-related disorder

Pathogenic:1

Apr 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCG5 c.1166G>A variant is predicted to result in the amino acid substitution p.Arg389His. This variant has been reported in multiple individuals with sitosterolemia and has been observed to segregate with disease in families (Lee et al. 2001. PubMed ID: 11138003; Niu et al. 2010. PubMed ID: 20521169; Tada et al. 2015. PubMed ID: 25665839; Yagasaki et al. 2017. PubMed ID: 28771437; Pek et al. 2018. PubMed ID: 29353225; Tada et al. 2018. PubMed ID: 30007774; Nomura et al. 2020. PubMed ID: 32862661; Reeskamp et al. 2020. PubMed ID: 32088153). This variant is reported in 0.21% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Sitosterolemia

Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 389 of the ABCG5 protein (p.Arg389His). This variant is present in population databases (rs119480069, gnomAD 0.2%). This missense change has been observed in individual(s) with sitosterolemia (PMID: 11138003, 15375183, 20521169, 20543520, 25665839, 28203044, 28771437, 30985648, 31060161). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Asian ancestry (PMID: 15375183, 30985648). ClinVar contains an entry for this variant (Variation ID: 4980). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Sep 05, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R389H pathogenic mutation (also known as c.1166G>A), located in coding exon 9 of the ABCG5 gene, results from a G to A substitution at nucleotide position 1166. The arginine at codon 389 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in the homozygous and compound heterozygous states in several individuals and families affected with sitosterolemia, being reported as a common cause of disease in Asian populations (Lee MH et al. Nat Genet, 2001 Jan;27:79-83; Wang J et al. J Lipid Res, 2004 Dec;45:2361-7; Niu DM et al. J Inherit Metab Dis, 2010 Aug;33:437-43; Tada H et al. JIMD Rep, 2015 Feb;21:115-22; Ono S et al. Clin Pediatr Endocrinol, 2017 Jan;26:17-23; Yagasaki H et al. J Pediatr Endocrinol Metab, 2017 Aug;30:1007-1011; Huang D et al. Medicine (Baltimore), 2019 Apr;98:e15013; Nomura A et al. Circ Genom Precis Med, 2020 10;13:417-423; Yamada Y et al. CJC Open, 2021 Aug;3:1085-1088). An in vitro study suggested this alteration may impact protein function (Graf GA et al. J Biol Chem, 2004 Jun;279:24881-8). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

.;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.18

T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.1

M;M

PhyloP100

7.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

N;.

REVEL

Pathogenic

0.65

Sift

Benign

0.095

T;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.95

MVP

0.92

MPC

0.46

ClinPred

0.31

GERP RS

5.9

Varity_R

0.56

gMVP

0.88

Mutation Taster

=148/152

disease causing (ClinVar)

(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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2-43824071-C-T

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