chr2-43812831-C-G

Variant names:

• chr2-43812831-C-G
• rs114868704
• NM_022436.3:c.*285G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022436.3(ABCG5):​c.*285G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00672 in 370,858 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (13 hom.)
• Consequence: ABCG5 NM_022436.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.462
• Publications: 2 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-43812831-C-G is Benign according to our data. Variant chr2-43812831-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 336033.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00643 (979/152230) while in subpopulation NFE AF = 0.00956 (650/68020). AF 95% confidence interval is 0.00895. There are 3 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.*285G>C		3_prime_UTR	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2307C>G		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2307C>G		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.*285G>C		3_prime_UTR	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2762G>C		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000644754.1		n.2625G>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.00644 AC: 979 AN: 152112 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00971

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00955

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00693 AC: 1514 AN: 218628 Hom.: 13 Cov.: 0 AF XY: 0.00672 AC XY: 760 AN XY: 113146

African (AFR) AF: 0.00121 AC: 9 AN: 7432

American (AMR) AF: 0.00427 AC: 35 AN: 8188

Ashkenazi Jewish (ASJ) AF: 0.000414 AC: 3 AN: 7250

East Asian (EAS) AF: 0.00 AC: 0 AN: 14146

South Asian (SAS) AF: 0.00731 AC: 159 AN: 21752

European-Finnish (FIN) AF: 0.00851 AC: 96 AN: 11278

Middle Eastern (MID) AF: 0.00102 AC: 1 AN: 978

European-Non Finnish (NFE) AF: 0.00837 AC: 1125 AN: 134354

Other (OTH) AF: 0.00649 AC: 86 AN: 13250

GnomAD4 genome AF: 0.00643 AC: 979 AN: 152230 Hom.: 3 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74424

African (AFR) AF: 0.00188 AC: 78 AN: 41534

American (AMR) AF: 0.00648 AC: 99 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00664 AC: 32 AN: 4816

European-Finnish (FIN) AF: 0.00971 AC: 103 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00956 AC: 650 AN: 68020

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00337 Hom.: 0

Bravo AF: 0.00524

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Sitosterolemia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.57
PhyloP100		-0.46
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: rs114868704; hg19: chr2-44039970;