2-43822924-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_022436.3(ABCG5):c.1336C>T(p.Arg446*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00011 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ABCG5
NM_022436.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 5.11

Publications

53 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-43822924-G-A is Pathogenic according to our data. Variant chr2-43822924-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022436.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCG5	NM_022436.3	MANE Select	c.1336C>T	p.Arg446*	stop_gained	Exon 10 of 13	NP_071881.1
DYNC2LI1	NM_001348913.2		c.*16-4462G>A		intron	N/A	NP_001335842.1
DYNC2LI1	NM_001348912.2		c.*16-4462G>A		intron	N/A	NP_001335841.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.1336C>T	p.Arg446*	stop_gained	Exon 10 of 13	ENSP00000384513.2
ABCG5	ENST00000486512.5	TSL:1	n.1857C>T		non_coding_transcript_exon	Exon 6 of 9
ABCG5	ENST00000409962.1	TSL:2	n.1619C>T		non_coding_transcript_exon	Exon 6 of 9

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00136

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000179

AC:

AN:

250704

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000971

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.000112

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.000454

AC:

AN:

39688

South Asian (SAS)

AF:

0.000394

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000728

AC:

AN:

1111932

Other (OTH)

AF:

0.000199

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000125

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41518

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00136

AC:

AN:

5140

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000350

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sitosterolemia 2

Pathogenic:9

May 25, 2022

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 15, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Aug 28, 2020

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Jan 16, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4, PM3, PP1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Null variant in a gene where loss of function (LOF) is a known mechanism of disease.;For recessive disorders, detected in trans with a pathogenic variant.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Aug 21, 2024

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:5

Jul 28, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a variant on the opposite allele (in trans) in in patients with sitosterolemia in published literature (Kratz et al., 2007; Rios et al., 2010; Wang et al., 2014; Buonuomo et al., 2017; Hu et al., 2021); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21729603, 27884173, 26813946, 34426522, 25525159, 31589614, 32041611, 32862661, 20521169, 17228349, 19111681, 30528907, 29055934, 28521186, 25665839, 33217533, 29353225, 33269076, 17976197, 24166850, 20719861, 31060161)

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM3_very_strong, PVS1

Oct 20, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Sitosterolemia

Pathogenic:4

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ABCG5 c.1336C>T (p.Arg446Ter) variant is a stop-gained variant that has been reported in seven studies in which it is found in a total of 11 individuals with sitosterolemia, including four in a homozygous state (of which three are related) and six in a compound heterozygous state. The variant was also detected in a compound heterozygous state in an asymptomatic sibling (Mannucci et al. 2007; Kratz et al. 2007; Nui et al. 2010; Rios et al. 2010; Park et al. 2014; Tada et al. 2015; Li et al. 2016). Control data are unavailable for the p.Arg446Ter variant, which is reported at a frequency of 0.00071 in the East Asian population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Arg446Ter variant is classified as pathogenic for sitosterolemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg446*) in the ABCG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCG5 are known to be pathogenic (PMID: 11138003, 25665839). This variant is present in population databases (rs199689137, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with sitosterolemia (PMID: 34304999, 34887220, 34969652). ClinVar contains an entry for this variant (Variation ID: 30485). For these reasons, this variant has been classified as Pathogenic.

Sep 06, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg446X variant in ABCG5 has been reported in at least 10 individuals with sitosterolemia, all of whom were homozygous or compound heterozygous, and segre gated with disease in 7 affected family members from 4 families (Kratz 2007, Man nucci 2007, Togo 2009, Rios 2010, Niu 2010, Wang 2011, Park 2014, Wang 2014, Tad a 2015, Li 2016, Pek 2017, Buonuomo 2017, Fang 2018). This variant has also been identified in 0.09% (16/18858) of East Asian chromosomes by gnomAD (http://gnom ad.broadinstitute.org). However, this frequency is low enough to be consistent w ith a recessive carrier frequency. This nonsense variant leads to a premature te rmination codon at position 446, which is predicted to lead to a truncated or ab sent protein. Loss of function of the ABCG5 gene is an established disease mecha nism in autosomal recessive sitosterolemia; however, this condition is known to have variable expressivity and reduced penetrance. In summary, this variant meet s criteria to be classified as pathogenic for autosomal recessive sitosterolemia based on case observations, segregation studies, and predicted impact on protei n. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PP1_Strong.

Sep 01, 2013

Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Sitosterolemia 1

Pathogenic:1

Apr 22, 2022

Molecular Genetics, Royal Melbourne Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature termination codon at position 446 in exon 10 (of 13) of ABCG5 (p.Arg446*). It is expected to result in an absent or disrupted protein product. Loss of function is an established mechanism of disease for ABCG5 in autosomal recessive sitosterolaemia (PVS1). It is present in a large population cohort at a frequency of 0.02% (rs199689137, 48/282,080 alleles in gnomAD v2.1.1), and is most prevalent in the East Asian population with a frequency of 0.09% (17/19,940 alleles). The variant has been reported in multiple individuals diagnosed with sitosterolaemia, all of whom were homozygous or compound heterozygous with a second pathogenic variant in ABCG5 (PMID: 19111681, 20719861, 24166850, 26813946, 28521186 - PM3_VeryStrong), and segregated in affected family members in multiple families (PMID: 17976197, 24166850 - PP1_Strong). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong, PP1_Strong.

Cardiovascular phenotype

Pathogenic:1

Aug 01, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1336C>T (p.R446*) alteration, located in exon 10 (coding exon 10) of the ABCG5 gene, consists of a C to T substitution at nucleotide position 1336. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 446. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.017% (48/282080) total alleles studied. The highest observed frequency was 0.085% (17/19940) of East Asian alleles. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals and families affected with sitosterolemia (Mannucci, 2007; Niu, 2010; Wang, 2014; Bazerbachi, 2017; Buonuomo, 2017; Veit, 2019; Wang, 2019; Frederiksen, 2021; Kaya, 2021; Zhang, 2022; Xia, 2022). Based on the available evidence, this alteration is classified as pathogenic.

Short-rib thoracic dysplasia 15 with polydactyly

Pathogenic:1

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

PhyloP100

5.1

Vest4

0.99

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over