rs119479067

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_022436.3(ABCG5):ā€‹c.1256G>Cā€‹(p.Arg419Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R419C) has been classified as Likely pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

ABCG5
NM_022436.3 missense

Scores

7
10
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.72
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1
In a helix (size 38) in uniprot entity ABCG5_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_022436.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-43823982-G-A is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 2-43823981-C-G is Pathogenic according to our data. Variant chr2-43823981-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 4979.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ABCG5NM_022436.3 linkc.1256G>C p.Arg419Pro missense_variant 9/13 ENST00000405322.8 NP_071881.1 Q9H222-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ABCG5ENST00000405322.8 linkc.1256G>C p.Arg419Pro missense_variant 9/131 NM_022436.3 ENSP00000384513.2 Q9H222-1
ABCG5ENST00000486512.5 linkn.1777G>C non_coding_transcript_exon_variant 5/91
ABCG5ENST00000409962.1 linkn.1539G>C non_coding_transcript_exon_variant 5/92
ABCG5ENST00000644754.1 linkn.1640G>C non_coding_transcript_exon_variant 6/10

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Sitosterolemia 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2001- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;D
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.89
.;D
M_CAP
Uncertain
0.26
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Benign
0.45
T
PROVEAN
Uncertain
-4.1
D;.
REVEL
Pathogenic
0.70
Sift
Uncertain
0.027
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.96
MutPred
0.93
Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP
0.90
MPC
0.49
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.99
gMVP
0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs119479067; hg19: chr2-44051120; API