rs727502773

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_005506.4(SCARB2):c.434_435dupAG(p.Trp146SerfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SCARB2
NM_005506.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:2

Conservation

PhyloP100: -0.341

Publications

9 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-76179693-A-ACT is Pathogenic according to our data. Variant chr4-76179693-A-ACT is described in ClinVar as Pathogenic. ClinVar VariationId is 7377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SCARB2	NM_005506.4 link	c.434_435dupAG	p.Trp146SerfsTer16	frameshift_variant	Exon 4 of 12	ENST00000264896.8	NP_005497.1
SCARB2	XM_047416429.1 link	c.-41_-40dupAG		5_prime_UTR_variant	Exon 4 of 12		XP_047272385.1
SCARB2	XM_047416430.1 link	c.-41_-40dupAG		5_prime_UTR_variant	Exon 4 of 12		XP_047272386.1
SCARB2	NM_001204255.2 link	c.276-3785_276-3784dupAG		intron_variant	Intron 2 of 8		NP_001191184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8 link	c.434_435dupAG	p.Trp146SerfsTer16	frameshift_variant	Exon 4 of 12	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000797

AC:

AN:

251012

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

221

AN:

1461216

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726974

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000192

AC:

213

AN:

1111622

Other (OTH)

AF:

0.0000662

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000151

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000196

Hom.:

Bravo

AF:

0.000121

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Action myoclonus-renal failure syndrome

Pathogenic:3Other:2

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Pathogenic and reported on 04-23-2020 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Mar 27, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Mar 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Inborn genetic diseases

Pathogenic:1

Sep 28, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.434_435dupAG pathogenic mutation, located in coding exon 4 of the SCARB2 gene, results from a duplication of AG at nucleotide position 434, causing a translational frameshift with a predicted alternate stop codon (p.W146Sfs*16). This mutation was first reported in a homozygous individual with action myoclonus-renal failure syndrome (Berkovic SF et al. Am. J. Hum. Genet., 2008 Mar;82:673-84). It was also detected in conjuction with a second SCARB2 alteration in a 22-year-old female with steroid resistant nephrotic syndrome, tremor and ataxia, suspected action myoclonus-renal failure syndrome, and focal segmental glomerulosclerosis on biopsy; however, the phase of the alterations was not provided (Sen ES et al. J. Med. Genet., 2017 Aug; doi: 10.1136/jmedgenet-2017-104811). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

not provided

Pathogenic:1

Jan 06, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate protein retention in the endoplasmic reticulum as well as inability to bind beta-glucocerebrosidase (Blanz et al., 2010); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29941711, 15364701, 24389070, 23659519, 22884962, 29655203, 19933215, 18308289)

Progressive myoclonic epilepsy

Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp146Serfs*16) in the SCARB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCARB2 are known to be pathogenic (PMID: 19847901). This variant is present in population databases (rs727502773, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with SCARB2-related conditions (PMID: 18308289). This variant is also known as c.435_436insAG. ClinVar contains an entry for this variant (Variation ID: 7377). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.34

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over