2-43812594-C-T

Variant names:

• chr2-43812594-C-T
• rs77105521
• NM_022436.3:c.*522G>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.*522G>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 0.176 in 169,228 control chromosomes in the GnomAD database, including 2,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2607 hom., cov: 31)
  • Exomes 𝑓: 0.15 (251 hom.)
• Consequence: ABCG5 NM_022436.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.323
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-43812594-C-T is Benign according to our data. Variant chr2-43812594-C-T is described in ClinVar as Benign. ClinVar VariationId is 336027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 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.*522G>A		3_prime_UTR	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2070C>T		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2070C>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.*522G>A		3_prime_UTR	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2999G>A		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000644754.1		n.2862G>A		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27205 AN: 151814 Hom.: 2595 Cov.: 31

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.0199

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.148 AC: 2568 AN: 17296 Hom.: 251 Cov.: 0 AF XY: 0.150 AC XY: 1316 AN XY: 8762

African (AFR) AF: 0.176 AC: 18 AN: 102

American (AMR) AF: 0.139 AC: 360 AN: 2594

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 38 AN: 214

East Asian (EAS) AF: 0.0106 AC: 11 AN: 1042

South Asian (SAS) AF: 0.175 AC: 323 AN: 1844

European-Finnish (FIN) AF: 0.156 AC: 76 AN: 488

Middle Eastern (MID) AF: 0.167 AC: 8 AN: 48

European-Non Finnish (NFE) AF: 0.157 AC: 1586 AN: 10124

Other (OTH) AF: 0.176 AC: 148 AN: 840

GnomAD4 genome AF: 0.179 AC: 27253 AN: 151932 Hom.: 2607 Cov.: 31 AF XY: 0.179 AC XY: 13265 AN XY: 74272

African (AFR) AF: 0.219 AC: 9056 AN: 41394

American (AMR) AF: 0.171 AC: 2603 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 654 AN: 3470

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5176

South Asian (SAS) AF: 0.198 AC: 956 AN: 4824

European-Finnish (FIN) AF: 0.179 AC: 1887 AN: 10550

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11414 AN: 67952

Other (OTH) AF: 0.191 AC: 403 AN: 2106

Alfa AF: 0.178 Hom.: 691

Bravo AF: 0.178

ClinVar

ClinVar submissions as Germline

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	-0.84
CADD	Benign	1.4
DANN	Benign	0.54
PhyloP100		-0.32
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: rs77105521; hg19: chr2-44039733;