rs376140340

Variant names:

• chr2-43812891-C-A
• rs376140340
• NM_022436.3:c.*225G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_022436.3(ABCG5):​c.*225G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 552,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: ABCG5 NM_022436.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.929
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• Ellis-van Creveld syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.*225G>T		3_prime_UTR	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2367C>A		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2367C>A		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.*225G>T		3_prime_UTR	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2702G>T		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000882115.1		c.*225G>T		3_prime_UTR	Exon 13 of 13	ENSP00000552174.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 88 AN: 400262 Hom.: 1 Cov.: 0 AF XY: 0.000318 AC XY: 67 AN XY: 210484

African (AFR) AF: 0.00 AC: 0 AN: 11552

American (AMR) AF: 0.00 AC: 0 AN: 16576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12432

East Asian (EAS) AF: 0.00 AC: 0 AN: 27328

South Asian (SAS) AF: 0.00200 AC: 83 AN: 41528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1752

European-Non Finnish (NFE) AF: 0.00000416 AC: 1 AN: 240454

Other (OTH) AF: 0.000171 AC: 4 AN: 23358

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74432

African (AFR) AF: 0.00 AC: 0 AN: 41486

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Sitosterolemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.0
DANN	Benign	0.69
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism

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: rs376140340; hg19: chr2-44040030;