rs2278357

Variant names:

• chr2-43812700-C-T
• rs2278357
• NM_022436.3:c.*416G>A

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.*416G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 202,312 control chromosomes in the GnomAD database, including 5,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4279 hom., cov: 32)
  • Exomes 𝑓: 0.16 (750 hom.)
• Consequence: ABCG5 NM_022436.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.86
• Publications: 14 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 (BayesDel_noAF=-0.88).
• BP6: Variant 2-43812700-C-T is Benign according to our data. Variant chr2-43812700-C-T is described in ClinVar as Benign. ClinVar VariationId is 336029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 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.*416G>A		3_prime_UTR	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2176C>T		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2176C>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.*416G>A		3_prime_UTR	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2893G>A		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000644754.1		n.2756G>A		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33312 AN: 152020 Hom.: 4266 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.202

GnomAD4 exome AF: 0.155 AC: 7791 AN: 50174 Hom.: 750 Cov.: 0 AF XY: 0.156 AC XY: 4013 AN XY: 25650

African (AFR) AF: 0.262 AC: 190 AN: 724

American (AMR) AF: 0.306 AC: 1072 AN: 3500

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 154 AN: 1044

East Asian (EAS) AF: 0.0962 AC: 261 AN: 2714

South Asian (SAS) AF: 0.220 AC: 1428 AN: 6486

European-Finnish (FIN) AF: 0.109 AC: 268 AN: 2468

Middle Eastern (MID) AF: 0.214 AC: 39 AN: 182

European-Non Finnish (NFE) AF: 0.132 AC: 4027 AN: 30438

Other (OTH) AF: 0.134 AC: 352 AN: 2618

GnomAD4 genome AF: 0.219 AC: 33358 AN: 152138 Hom.: 4279 Cov.: 32 AF XY: 0.219 AC XY: 16289 AN XY: 74382

African (AFR) AF: 0.339 AC: 14061 AN: 41480

American (AMR) AF: 0.276 AC: 4211 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3470

East Asian (EAS) AF: 0.113 AC: 587 AN: 5182

South Asian (SAS) AF: 0.262 AC: 1256 AN: 4802

European-Finnish (FIN) AF: 0.124 AC: 1312 AN: 10594

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10696 AN: 68014

Other (OTH) AF: 0.203 AC: 428 AN: 2112

Alfa AF: 0.183 Hom.: 4901

Bravo AF: 0.235

Asia WGS AF: 0.185 AC: 645 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.25
DANN	Benign	0.65
PhyloP100		-1.9
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2278357;

hg19: chr2-44039839;