rs6720173

chr2-43813262-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.37

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]

DYNC2LI1 (HGNC:):

ACMG classification

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	UniProt
ABCG5	NM_022436.3	c.1810C>G	p.Gln604Glu	missense_variant	13/13	ENST00000405322.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCG5	ENST00000405322.8	c.1810C>G	p.Gln604Glu	missense_variant	13/13	1	NM_022436.3	P1
ABCG5	ENST00000486512.5	n.2331C>G		non_coding_transcript_exon_variant	9/9	1
ABCG5	ENST00000409962.1	n.2093C>G		non_coding_transcript_exon_variant	9/9	2
ABCG5	ENST00000644754.1	n.2194C>G		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32178 AN: 152082 Hom.: 3874 Cov.: 32

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

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.: 31 AF XY: 0.178 AC XY: 129043 AN XY: 726402

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.: 32 AF XY: 0.212 AC XY: 15751 AN XY: 74424

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

Sitosterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

This variant is associated with the following publications: (PMID: 12220438, 17827468, 20543520) -

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	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.78	P;P;P
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs6720173; hg19: chr2-44040401; COSMIC: COSV53183022; COSMIC: COSV53183022;