rs6720173

Positions:

chr2-43813262-G-C

Variant summary

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

The NM_022436.3(ABCG5):c.1810C>G(p.Gln604Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,612,154 control chromosomes in the GnomAD database, including 28,676 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3886 hom., cov: 32)

Exomes 𝑓: 0.18 ( 24790 hom. )

Consequence

ABCG5
NM_022436.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.37

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:

ABCG5 (HGNC:):

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 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=0.0031442046).

BP6

Variant 2-43813262-G-C is Benign according to our data. Variant chr2-43813262-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 336036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-43813262-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG5	NM_022436.3 linkuse as main transcript	c.1810C>G	p.Gln604Glu	missense_variant	13/13	ENST00000405322.8	NP_071881.1	Q9H222-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCG5	ENST00000405322.8 linkuse as main transcript	c.1810C>G	p.Gln604Glu	missense_variant	13/13	1	NM_022436.3	ENSP00000384513.2	Q9H222-1
ABCG5	ENST00000486512.5 linkuse as main transcript	n.2331C>G		non_coding_transcript_exon_variant	9/9	1
ABCG5	ENST00000409962.1 linkuse as main transcript	n.2093C>G		non_coding_transcript_exon_variant	9/9	2
ABCG5	ENST00000644754.1 linkuse as main transcript	n.2194C>G		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32178

AN:

152082

Hom.:

3874

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.272

Gnomad ASJ

AF:

0.187

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.262

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.188

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.197

GnomAD3 exomes

AF:

0.207

AC:

51752

AN:

249426

Hom.:

6210

AF XY:

0.202

AC XY:

27310

AN XY:

134930

show subpopulations

Gnomad AFR exome

AF:

0.309

Gnomad AMR exome

AF:

0.360

Gnomad ASJ exome

AF:

0.186

Gnomad EAS exome

AF:

0.114

Gnomad SAS exome

AF:

0.265

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.165

Gnomad OTH exome

AF:

0.189

GnomAD4 exome

AF:

0.177

AC:

257865

AN:

1459954

Hom.:

24790

Cov.:

AF XY:

0.178

AC XY:

129043

AN XY:

726402

show subpopulations

Gnomad4 AFR exome

AF:

0.312

Gnomad4 AMR exome

AF:

0.348

Gnomad4 ASJ exome

AF:

0.187

Gnomad4 EAS exome

AF:

0.118

Gnomad4 SAS exome

AF:

0.264

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.162

Gnomad4 OTH exome

AF:

0.182

GnomAD4 genome

AF:

0.212

AC:

32223

AN:

152200

Hom.:

3886

Cov.:

AF XY:

0.212

AC XY:

15751

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.308

Gnomad4 AMR

AF:

0.272

Gnomad4 ASJ

AF:

0.187

Gnomad4 EAS

AF:

0.114

Gnomad4 SAS

AF:

0.261

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.160

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.170

Hom.:

1748

Bravo

AF:

0.226

TwinsUK

AF:

0.163

AC:

604

ALSPAC

AF:

0.160

AC:

616

ESP6500AA

AF:

0.307

AC:

1353

ESP6500EA

AF:

0.161

AC:

1382

ExAC

AF:

0.206

AC:

25075

Asia WGS

AF:

0.182

AC:

636

AN:

3478

EpiCase

AF:

0.158

EpiControl

AF:

0.164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 24, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 12220438, 17827468, 20543520) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sitosterolemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Sitosterolemia 1

Benign:1

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. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 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

0.051

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.70

.;T

MetaRNN

Benign

0.0031

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.78

N;.

REVEL

Benign

0.075

Sift

Benign

0.37

T;.

Sift4G

Uncertain

0.049

D;.

Polyphen

0.067

B;B

Vest4

0.22

MPC

0.082

ClinPred

0.0081

GERP RS

3.9

Varity_R

0.12

gMVP

0.82

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

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