chr4-76161747-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005506.4(SCARB2):c.1403C>T(p.Thr468Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
SCARB2
NM_005506.4 missense
NM_005506.4 missense
Scores
1
12
6
Clinical Significance
Conservation
PhyloP100: 3.26
Genes affected
SCARB2 (HGNC:1665): (scavenger receptor class B member 2) The protein encoded by this gene is a type III glycoprotein that is located primarily in limiting membranes of lysosomes and endosomes. Earlier studies in mice and rat suggested that this protein may participate in membrane transportation and the reorganization of endosomal/lysosomal compartment. The protein deficiency in mice was reported to impair cell membrane transport processes and cause pelvic junction obstruction, deafness, and peripheral neuropathy. Further studies in human showed that this protein is a ubiquitously expressed protein and that it is involved in the pathogenesis of HFMD (hand, foot, and mouth disease) caused by enterovirus-71 and possibly by coxsackievirus A16. Mutations in this gene caused an autosomal recessive progressive myoclonic epilepsy-4 (EPM4), also known as action myoclonus-renal failure syndrome (AMRF). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCARB2 | NM_005506.4 | c.1403C>T | p.Thr468Ile | missense_variant | 12/12 | ENST00000264896.8 | |
SCARB2 | NM_001204255.2 | c.974C>T | p.Thr325Ile | missense_variant | 9/9 | ||
SCARB2 | XM_047416429.1 | c.929C>T | p.Thr310Ile | missense_variant | 12/12 | ||
SCARB2 | XM_047416430.1 | c.929C>T | p.Thr310Ile | missense_variant | 12/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCARB2 | ENST00000264896.8 | c.1403C>T | p.Thr468Ile | missense_variant | 12/12 | 1 | NM_005506.4 | P4 | |
ENST00000651366.1 | n.102+12481G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461854Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2022 | The c.1403C>T (p.T468I) alteration is located in exon 12 (coding exon 12) of the SCARB2 gene. This alteration results from a C to T substitution at nucleotide position 1403, causing the threonine (T) at amino acid position 468 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 21, 2014 | p.Thr468Ile (ACA>ATA): c.1403 C>T in exon 12 of the SCARB2 gene (NM_005506.3) A variant of unknown significance has been identified in the SCARB2 gene. The T468I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T468I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether the T468I variant is a pathogenic mutation or a rare benign variant.The variant is found in EPILEPSY panel(s). - |
Progressive myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 20, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
M;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;.;.;N
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;D
Sift4G
Uncertain
D;.;.;.;.;D
Polyphen
D;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at