chr2-43826984-G-A

Variant names:

• chr2-43826984-G-A
• rs4289236
• NM_022436.3:c.635-463C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022436.3(ABCG5):​c.635-463C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,222 control chromosomes in the GnomAD database, including 5,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.22 (5179 hom., cov: 32)
• Consequence: ABCG5 NM_022436.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.668
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG5	NM_022436.3	c.635-463C>T		intron_variant	Intron 5 of 12	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG5	ENST00000405322.8	c.635-463C>T		intron_variant	Intron 5 of 12	1	NM_022436.3	ENSP00000384513.2
ABCG5	ENST00000486512.5	n.1639+999C>T		intron_variant	Intron 4 of 8	1
ABCG5	ENST00000409962.1	n.1401+999C>T		intron_variant	Intron 4 of 8	2
ABCG5	ENST00000644754.1	n.1288+999C>T		intron_variant	Intron 4 of 9

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33999 AN: 152104 Hom.: 5169 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.217

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.223 AC: 34017 AN: 152222 Hom.: 5179 Cov.: 32 AF XY: 0.234 AC XY: 17408 AN XY: 74430

African (AFR) AF: 0.158 AC: 6578 AN: 41542

American (AMR) AF: 0.287 AC: 4390 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3470

East Asian (EAS) AF: 0.808 AC: 4179 AN: 5172

South Asian (SAS) AF: 0.530 AC: 2558 AN: 4822

European-Finnish (FIN) AF: 0.205 AC: 2172 AN: 10590

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.188 AC: 12816 AN: 68008

Other (OTH) AF: 0.240 AC: 508 AN: 2114

Alfa AF: 0.204 Hom.: 8108

Bravo AF: 0.222

Asia WGS AF: 0.580 AC: 2017 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.79
PhyloP100		-0.67
Mutation Taster		=100/0	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: rs4289236; hg19: chr2-44054123;