chr4-76161717-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_005506.4(SCARB2):​c.1433C>A​(p.Thr478Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SCARB2
NM_005506.4 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79
Variant links:
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 3 ACMG points.

PM1
In a mutagenesis_site Normal targeting of the protein to lysosomes. (size 0) in uniprot entity SCRB2_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3062665).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCARB2NM_005506.4 linkuse as main transcriptc.1433C>A p.Thr478Asn missense_variant 12/12 ENST00000264896.8
SCARB2NM_001204255.2 linkuse as main transcriptc.1004C>A p.Thr335Asn missense_variant 9/9
SCARB2XM_047416429.1 linkuse as main transcriptc.959C>A p.Thr320Asn missense_variant 12/12
SCARB2XM_047416430.1 linkuse as main transcriptc.959C>A p.Thr320Asn missense_variant 12/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCARB2ENST00000264896.8 linkuse as main transcriptc.1433C>A p.Thr478Asn missense_variant 12/121 NM_005506.4 P4Q14108-1
ENST00000651366.1 linkuse as main transcriptn.102+12451G>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 27, 2021This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 478 of the SCARB2 protein (p.Thr478Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCARB2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.081
D
BayesDel_noAF
Benign
-0.12
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T;.;.;.;.;.
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.89
D;D;D;D;D;D
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.31
T;T;T;T;T;T
MetaSVM
Uncertain
-0.014
T
MutationAssessor
Benign
2.0
M;.;.;.;.;.
MutationTaster
Benign
0.99
N;N
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.1
N;.;.;.;.;N
REVEL
Benign
0.28
Sift
Uncertain
0.0080
D;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;.;.;.;.;D
Polyphen
0.99
D;.;.;.;.;.
Vest4
0.31
MutPred
0.28
Loss of glycosylation at T478 (P = 0.0528);.;.;.;.;.;
MVP
0.81
MPC
0.84
ClinPred
0.80
D
GERP RS
4.4
Varity_R
0.094
gMVP
0.42

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: chr4-77082870; API