4-76195788-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_005506.4(SCARB2):​c.194A>G​(p.Tyr65Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SCARB2
NM_005506.4 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.83
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]

Genome browser will be placed here

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=0.26622885).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000158 (24/152260) while in subpopulation SAS AF= 0.00186 (9/4828). AF 95% confidence interval is 0.000972. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SCARB2NM_005506.4 linkc.194A>G p.Tyr65Cys missense_variant Exon 2 of 12 ENST00000264896.8 NP_005497.1 Q14108-1A0A024RDG6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SCARB2ENST00000264896.8 linkc.194A>G p.Tyr65Cys missense_variant Exon 2 of 12 1 NM_005506.4 ENSP00000264896.2 Q14108-1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152142
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:
0.00207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000221
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000290
AC:
73
AN:
251420
Hom.:
0
AF XY:
0.000346
AC XY:
47
AN XY:
135880
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00183
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000205
AC:
299
AN:
1461522
Hom.:
0
Cov.:
30
AF XY:
0.000264
AC XY:
192
AN XY:
727098
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00180
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000109
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000158
AC:
24
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74448
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:
0.00186
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000221
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000145
Hom.:
0
Bravo
AF:
0.000106
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000329
AC:
40
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000218
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Action myoclonus-renal failure syndrome Uncertain:3
Sep 07, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The missense c.194A>G p.Tyr65Cys variant in SCARB2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Tyr65Cys variant is present with allele frequency of 0.03% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance multiple submissions. Multiple lines of computational evidence Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position in SCARB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Tyr at position 65 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. In absence of another reportable variant in SCARB2 gene, the molecular diagnosis is not confirmed. -

not provided Uncertain:1
Sep 24, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Progressive myoclonic epilepsy Uncertain:1
Jan 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 65 of the SCARB2 protein (p.Tyr65Cys). This variant is present in population databases (rs138955932, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SCARB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 206708). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCARB2 protein function with a positive predictive value of 80%. 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
Uncertain
0.44
BayesDel_addAF
Uncertain
0.084
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;.;.;.;.;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.27
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.79
D
MutationAssessor
Pathogenic
3.5
H;.;.;.;.;H;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-7.4
D;.;.;.;.;D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;.;.;.;.;D;.
Sift4G
Pathogenic
0.0010
D;.;.;.;.;D;.
Polyphen
1.0
D;.;.;.;.;.;.
Vest4
0.97
MVP
0.92
MPC
0.97
ClinPred
0.70
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs138955932; hg19: chr4-77116941; API