NM_005506.4:c.475A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005506.4(SCARB2):c.475A>G(p.Met159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00924 in 1,614,106 control chromosomes in the GnomAD database, including 98 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 90 hom. )

Consequence

SCARB2
NM_005506.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.140

Publications

16 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=0.0078088045).

BP6

Variant 4-76179654-T-C is Benign according to our data. Variant chr4-76179654-T-C is described in ClinVar as Benign. ClinVar VariationId is 206702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00836 (1273/152336) while in subpopulation NFE AF = 0.0126 (859/68036). AF 95% confidence interval is 0.0119. There are 8 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCARB2	NM_005506.4	MANE Select	c.475A>G	p.Met159Val	missense	Exon 4 of 12	NP_005497.1
	SCARB2	NM_001204255.2		c.276-3744A>G		intron	N/A	NP_001191184.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCARB2	ENST00000264896.8	TSL:1 MANE Select	c.475A>G	p.Met159Val	missense	Exon 4 of 12	ENSP00000264896.2
SCARB2	ENST00000638295.1	TSL:5	c.1A>G	p.Met1?	start_lost	Exon 4 of 12	ENSP00000492288.1
SCARB2	ENST00000640634.1	TSL:5	c.595A>G	p.Met199Val	missense	Exon 5 of 13	ENSP00000492737.1

Frequencies

GnomAD3 genomes

AF:

0.00837

AC:

1274

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00909

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00932

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0126

Gnomad OTH

AF:

0.0139

GnomAD2 exomes

AF:

0.00861

AC:

2163

AN:

251304

AF XY:

0.00872

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.00778

Gnomad ASJ exome

AF:

0.0129

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00990

Gnomad NFE exome

AF:

0.0124

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.00933

AC:

13636

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

6810

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

33478

American (AMR)

AF:

0.00807

AC:

361

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

345

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.00136

AC:

117

AN:

86258

European-Finnish (FIN)

AF:

0.0107

AC:

570

AN:

53378

Middle Eastern (MID)

AF:

0.0255

AC:

147

AN:

5768

European-Non Finnish (NFE)

AF:

0.0102

AC:

11383

AN:

1111934

Other (OTH)

AF:

0.0104

AC:

629

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

736

1473

2209

2946

3682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.00836

AC:

1273

AN:

152336

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

614

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00209

AC:

AN:

41574

American (AMR)

AF:

0.00908

AC:

139

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00932

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0126

AC:

859

AN:

68036

Other (OTH)

AF:

0.0137

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

130

194

259

324

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0107

Hom.:

Bravo

AF:

0.00824

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.00896

AC:

1088

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0135

EpiControl

AF:

0.0136

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Action myoclonus-renal failure syndrome (1)

Focal segmental glomerulosclerosis (1)

Inborn genetic diseases (1)

Progressive myoclonic epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.8

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.12

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

PhyloP100

-0.14

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.43

REVEL

Benign

0.13

Sift

Benign

0.45

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.11

MVP

0.40

MPC

0.24

ClinPred

0.00036

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.53

Mutation Taster

=98/2

polymorphism

(source)

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

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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

Computational scores

Splicing

Publications

Other links and lift over