2-43813127-T-G

Variant names:

• chr2-43813127-T-G
• NM_022436.3:c.1945A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022436.3(ABCG5):​c.1945A>C​(p.Ile649Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,099,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25212383).

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.1945A>C	p.Ile649Leu	missense	Exon 13 of 13	NP_071881.1	Q9H222-1
	DYNC2LI1	NM_001348913.2		c.*15+2603T>G		intron	N/A	NP_001335842.1
	DYNC2LI1	NM_001348912.2		c.*15+2603T>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.1945A>C	p.Ile649Leu	missense	Exon 13 of 13	ENSP00000384513.2	Q9H222-1
	ABCG5	ENST00000486512.5	TSL:1	n.2466A>C		non_coding_transcript_exon	Exon 9 of 9
	ABCG5	ENST00000882115.1		c.1810A>C	p.Ile604Leu	missense	Exon 13 of 13	ENSP00000552174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000446 AC: 49 AN: 1099226 Hom.: 0 Cov.: 16 AF XY: 0.0000390 AC XY: 22 AN XY: 564024

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000382 AC: 1 AN: 26162

American (AMR) AF: 0.00 AC: 0 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23818

East Asian (EAS) AF: 0.00 AC: 0 AN: 38024

South Asian (SAS) AF: 0.00 AC: 0 AN: 78818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.0000601 AC: 47 AN: 781608

Other (OTH) AF: 0.0000207 AC: 1 AN: 48204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.090
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.20	B
Vest4		0.14
MutPred		0.30		Gain of catalytic residue at I649 (P = 0.0244)
MVP		0.73
MPC		0.088
ClinPred		0.42	T
GERP RS		2.6
Varity_R		0.14
gMVP		0.69
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr2-44040266;