chr2-43813262-G-C

Variant names:

• chr2-43813262-G-C
• rs6720173
• NM_022436.3:c.1810C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:11
• Conservation: PhyloP100: 3.37
• Publications: 80 publications found

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: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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 336036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	NM_022436.3	MANE Select	c.1810C>G	p.Gln604Glu	missense	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2738G>C		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2738G>C		intron	N/A	NP_001335841.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.1810C>G	p.Gln604Glu	missense	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2331C>G		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000882115.1		c.1675C>G	p.Gln559Glu	missense	Exon 13 of 13	ENSP00000552174.1

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

GnomAD2 exomes AF: 0.207 AC: 51752 AN: 249426 AF XY: 0.202

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 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

African (AFR) AF: 0.312 AC: 10417 AN: 33436

American (AMR) AF: 0.348 AC: 15515 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4894 AN: 26104

East Asian (EAS) AF: 0.118 AC: 4674 AN: 39682

South Asian (SAS) AF: 0.264 AC: 22728 AN: 86136

European-Finnish (FIN) AF: 0.133 AC: 7088 AN: 53388

Middle Eastern (MID) AF: 0.217 AC: 1253 AN: 5766

European-Non Finnish (NFE) AF: 0.162 AC: 180297 AN: 1110468

Other (OTH) AF: 0.182 AC: 10999 AN: 60330

GnomAD4 genome AF: 0.212 AC: 32223 AN: 152200 Hom.: 3886 Cov.: 32 AF XY: 0.212 AC XY: 15751 AN XY: 74424

African (AFR) AF: 0.308 AC: 12800 AN: 41514

American (AMR) AF: 0.272 AC: 4159 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 650 AN: 3468

East Asian (EAS) AF: 0.114 AC: 589 AN: 5180

South Asian (SAS) AF: 0.261 AC: 1258 AN: 4820

European-Finnish (FIN) AF: 0.124 AC: 1316 AN: 10602

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10857 AN: 68004

Other (OTH) AF: 0.198 AC: 418 AN: 2116

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Sitosterolemia (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Sitosterolemia 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.4
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
Vest4		0.22
MPC		0.082
ClinPred		0.0081	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.82
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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