chr2-43820391-C-T

Variant names:

• chr2-43820391-C-T
• rs4148189
• NM_022436.3:c.1464-291G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022436.3(ABCG5):​c.1464-291G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 152,062 control chromosomes in the GnomAD database, including 6,956 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.24 (6956 hom., cov: 32)
• Consequence: ABCG5 NM_022436.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.371
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-43820391-C-T is Benign according to our data. Variant chr2-43820391-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.518 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.1464-291G>A		intron	N/A	NP_071881.1
	DYNC2LI1	NM_001348913.2		c.*16-6995C>T		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*16-6995C>T		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.1464-291G>A		intron	N/A	ENSP00000384513.2
	ABCG5	ENST00000486512.5	TSL:1	n.1985-291G>A		intron	N/A
	ABCG5	ENST00000882115.1		c.1329-291G>A		intron	N/A	ENSP00000552174.1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36498 AN: 151944 Hom.: 6930 Cov.: 32

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.241 AC: 36580 AN: 152062 Hom.: 6956 Cov.: 32 AF XY: 0.238 AC XY: 17654 AN XY: 74326

African (AFR) AF: 0.524 AC: 21701 AN: 41446

American (AMR) AF: 0.260 AC: 3975 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3468

East Asian (EAS) AF: 0.0567 AC: 294 AN: 5184

South Asian (SAS) AF: 0.179 AC: 863 AN: 4812

European-Finnish (FIN) AF: 0.103 AC: 1090 AN: 10586

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7678 AN: 67988

Other (OTH) AF: 0.199 AC: 420 AN: 2110

Alfa AF: 0.145 Hom.: 5203

Bravo AF: 0.265

Asia WGS AF: 0.166 AC: 579 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.47
PhyloP100		-0.37
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: rs4148189; hg19: chr2-44047530;