chr2-43821981-G-A

Variant names:

• chr2-43821981-G-A
• rs4245786
• NM_022436.3:c.1463+816C>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.1463+816C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.777 in 151,986 control chromosomes in the GnomAD database, including 45,969 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 0.78 (45969 hom., cov: 30)
• Consequence: ABCG5 NM_022436.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.907 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	NM_022436.3	MANE Select	c.1463+816C>T		intron	N/A	NP_071881.1
	DYNC2LI1	NM_001348913.2		c.*16-5405G>A		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*16-5405G>A		intron	N/A	NP_001335841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCG5	ENST00000405322.8	TSL:1 MANE Select	c.1463+816C>T		intron	N/A	ENSP00000384513.2
	ABCG5	ENST00000486512.5	TSL:1	n.1984+816C>T		intron	N/A
	ABCG5	ENST00000409962.1	TSL:2	n.1746+816C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.777 AC: 117972 AN: 151868 Hom.: 45927 Cov.: 30

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.751

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.775

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

GnomAD4 genome AF: 0.777 AC: 118072 AN: 151986 Hom.: 45969 Cov.: 30 AF XY: 0.780 AC XY: 57961 AN XY: 74304

African (AFR) AF: 0.780 AC: 32299 AN: 41396

American (AMR) AF: 0.761 AC: 11632 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.751 AC: 2607 AN: 3470

East Asian (EAS) AF: 0.929 AC: 4803 AN: 5170

South Asian (SAS) AF: 0.746 AC: 3587 AN: 4808

European-Finnish (FIN) AF: 0.815 AC: 8620 AN: 10574

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.764 AC: 51961 AN: 67970

Other (OTH) AF: 0.775 AC: 1637 AN: 2112

Alfa AF: 0.767 Hom.: 85069

Bravo AF: 0.772

Asia WGS AF: 0.822 AC: 2859 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.9
DANN	Benign	0.80
PhyloP100		0.10
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: rs4245786; hg19: chr2-44049120;