Variant chr2-43813127-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

Variant links:

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]

ABCG5 links:

DYNC2LI1 (HGNC:):

DYNC2LI1 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
ABCG5	NM_022436.3 linkuse as main transcript	c.1945A>C	p.Ile649Leu	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 linkuse as main transcript	c.1945A>C	p.Ile649Leu	missense_variant	13/13	1	NM_022436.3	ENSP00000384513	P1	Q9H222-1
ABCG5	ENST00000486512.5 linkuse as main transcript	n.2466A>C		non_coding_transcript_exon_variant	9/9	1
ABCG5	ENST00000409962.1 linkuse as main transcript	n.2228A>C		non_coding_transcript_exon_variant	9/9	2
ABCG5	ENST00000644754.1 linkuse as main transcript	n.2329A>C		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1099226

Hom.:

Cov.:

AF XY:

0.0000390

AC XY:

AN XY:

564024

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.56

.;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

-0.089

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

0.72

D;D;N

PrimateAI

Uncertain

0.52

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over