chr2-43813130-G-A

Position:

• chr2-43813130-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022436.3(ABCG5):​c.1942C>T​(p.Leu648Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: ABCG5 NM_022436.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.133

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:):

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=0.09627256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCG5	NM_022436.3	c.1942C>T	p.Leu648Phe	missense_variant	13/13	ENST00000405322.8	NP_071881.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCG5	ENST00000405322.8	c.1942C>T	p.Leu648Phe	missense_variant	13/13	1	NM_022436.3	ENSP00000384513	P1
ABCG5	ENST00000486512.5	n.2463C>T		non_coding_transcript_exon_variant	9/9	1
ABCG5	ENST00000409962.1	n.2225C>T		non_coding_transcript_exon_variant	9/9	2
ABCG5	ENST00000644754.1	n.2326C>T		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 16

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2023

The p.L648F variant (also known as c.1942C>T), located in coding exon 13 of the ABCG5 gene, results from a C to T substitution at nucleotide position 1942. The leucine at codon 648 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.62	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.096	T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.81	L;L
MutationTaster	Benign	0.53	D;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.51	N;.
REVEL	Benign	0.15
Sift	Benign	0.17	T;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.012	B;B
Vest4		0.032
MutPred		0.27		Gain of MoRF binding (P = 0.1041);Gain of MoRF binding (P = 0.1041);
MVP		0.81
MPC		0.076
ClinPred		0.052	T
GERP RS		-2.0
Varity_R		0.093
gMVP		0.80

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: chr2-44040269;