NM_022436.3:c.1945A>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCG5	NM_022436.3	c.1945A>C	p.Ile649Leu	missense_variant	Exon 13 of 13	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCG5	ENST00000405322.8	c.1945A>C	p.Ile649Leu	missense_variant	Exon 13 of 13	1	NM_022436.3	ENSP00000384513.2
ABCG5	ENST00000486512.5	n.2466A>C		non_coding_transcript_exon_variant	Exon 9 of 9	1
ABCG5	ENST00000409962.1	n.2228A>C		non_coding_transcript_exon_variant	Exon 9 of 9	2
ABCG5	ENST00000644754.1	n.2329A>C		non_coding_transcript_exon_variant	Exon 10 of 10

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

Gnomad4 AFR exome AF: 0.0000382

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000601

Gnomad4 OTH exome AF: 0.0000207

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1945A>C (p.I649L) alteration is located in exon 13 (coding exon 13) of the ABCG5 gene. This alteration results from a A to C substitution at nucleotide position 1945, causing the isoleucine (I) at amino acid position 649 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Uncertain	-0.089	T
MutationAssessor	Benign	1.9	L;L
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;B
Vest4		0.14
MutPred		0.30		Gain of catalytic residue at I649 (P = 0.0244);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-44040266;