rs147159813

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_005506.4(SCARB2):c.445G>A(p.Val149Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,778 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 20 hom. )

Consequence

SCARB2
NM_005506.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: -0.696

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]

SCARB2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034089088).

BP6

Variant 4-76179684-C-T is Benign according to our data. Variant chr4-76179684-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206701.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=5, Benign=1}. Variant chr4-76179684-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00215 (328/152322) while in subpopulation AMR AF= 0.00516 (79/15300). AF 95% confidence interval is 0.00425. There are 1 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCARB2	NM_005506.4 linkuse as main transcript	c.445G>A	p.Val149Met	missense_variant	4/12	ENST00000264896.8
SCARB2	XM_047416429.1 linkuse as main transcript	c.-30G>A		5_prime_UTR_variant	4/12
SCARB2	XM_047416430.1 linkuse as main transcript	c.-30G>A		5_prime_UTR_variant	4/12
SCARB2	NM_001204255.2 linkuse as main transcript	c.276-3774G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCARB2	ENST00000264896.8 linkuse as main transcript	c.445G>A	p.Val149Met	missense_variant	4/12	1	NM_005506.4	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.103-20282C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00215

AC:

327

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00517

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00217

AC:

546

AN:

251082

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00288

AC:

4211

AN:

1461456

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

2063

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.00344

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.00215

AC:

328

AN:

152322

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00516

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00296

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00205

AC:

249

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00425

EpiControl

AF:

0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 06, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2021	This variant is associated with the following publications: (PMID: 18308289) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2017	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 07, 2020	- -

Action myoclonus-renal failure syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SCARB2 NM_005506 exon 4 p.Val149Met (c.445G>A): This variant has not been reported in the literature but is present in 0.3% (437/126510) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs147159813). This variant is present in ClinVar (Variation ID:206701). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

SCARB2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Progressive myoclonic epilepsy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

Cadd

Benign

1.4

Dann

Benign

0.95

DEOGEN2

Benign

0.081

T;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.67

T;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.34

N;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.43

N;.;.;.;.

REVEL

Benign

0.082

Sift

Benign

0.14

T;.;.;.;.

Sift4G

Benign

0.23

T;.;.;.;.

Polyphen

0.047

B;.;.;.;.

Vest4

0.19

MVP

0.25

MPC

0.24

ClinPred

0.0019

GERP RS

-6.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.27

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over