NM_005506.4:c.1186G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005506.4(SCARB2):c.1186G>A(p.Val396Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,613,768 control chromosomes in the GnomAD database, including 266 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 120 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 146 hom. )

Consequence

SCARB2
NM_005506.4 missense, splice_region

Scores

Splicing: ADA: 0.0001160

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.333

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

action myoclonus-renal failure syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
progressive myoclonus epilepsy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Unverricht-Lundborg syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SCARB2 links:

ENSG00000286074 (HGNC:58820):

ENSG00000286074 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021950305).

BP6

Variant 4-76168404-C-T is Benign according to our data. Variant chr4-76168404-C-T is described in ClinVar as Benign. ClinVar VariationId is 259780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005506.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCARB2	NM_005506.4	MANE Select	c.1186G>A	p.Val396Ile	missense splice_region	Exon 9 of 12	NP_005497.1
	SCARB2	NM_001204255.2		c.757G>A	p.Val253Ile	missense splice_region	Exon 6 of 9	NP_001191184.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCARB2	ENST00000264896.8	TSL:1 MANE Select	c.1186G>A	p.Val396Ile	missense splice_region	Exon 9 of 12	ENSP00000264896.2
SCARB2	ENST00000640634.1	TSL:5	c.1306G>A	p.Val436Ile	missense splice_region	Exon 10 of 13	ENSP00000492737.1
SCARB2	ENST00000639145.1	TSL:5	c.1177G>A	p.Val393Ile	missense splice_region	Exon 9 of 12	ENSP00000492831.1

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3505

AN:

152190

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0800

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00772

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00607

AC:

1526

AN:

251368

AF XY:

0.00425

show subpopulations

Gnomad AFR exome

AF:

0.0829

Gnomad AMR exome

AF:

0.00387

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00235

AC:

3435

AN:

1461460

Hom.:

146

Cov.:

AF XY:

0.00199

AC XY:

1446

AN XY:

727086

show subpopulations

African (AFR)

AF:

0.0829

AC:

2774

AN:

33444

American (AMR)

AF:

0.00474

AC:

212

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00486

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000999

AC:

111

AN:

1111664

Other (OTH)

AF:

0.00484

AC:

292

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

164

328

492

656

820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0230

AC:

3508

AN:

152308

Hom.:

120

Cov.:

AF XY:

0.0224

AC XY:

1666

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0799

AC:

3318

AN:

41546

American (AMR)

AF:

0.00771

AC:

118

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000367

AC:

AN:

68030

Other (OTH)

AF:

0.0213

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

172

344

516

688

860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00841

Hom.:

Bravo

AF:

0.0264

ESP6500AA

AF:

0.0747

AC:

329

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00753

AC:

914

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 25, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Jun 21, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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.

Focal segmental glomerulosclerosis

Benign:1

Jun 04, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Progressive myoclonic epilepsy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.26

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.11

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0022

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

PhyloP100

-0.33

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.29

REVEL

Benign

0.052

Sift

Benign

0.41

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.059

MVP

0.17

MPC

0.19

ClinPred

0.00047

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.047

gMVP

0.33

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.010

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over