rs121909118

Positions:

chr4-76174276-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_005506.4(SCARB2):c.862C>T(p.Gln288Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SCARB2
NM_005506.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 1.02

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 Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-76174276-G-A is Pathogenic according to our data. Variant chr4-76174276-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCARB2	NM_005506.4 linkuse as main transcript	c.862C>T	p.Gln288Ter	stop_gained	7/12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2 linkuse as main transcript	c.433C>T	p.Gln145Ter	stop_gained	4/9		NP_001191184.1
SCARB2	XM_047416429.1 linkuse as main transcript	c.388C>T	p.Gln130Ter	stop_gained	7/12		XP_047272385.1
SCARB2	XM_047416430.1 linkuse as main transcript	c.388C>T	p.Gln130Ter	stop_gained	7/12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8 linkuse as main transcript	c.862C>T	p.Gln288Ter	stop_gained	7/12	1	NM_005506.4	ENSP00000264896	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.102+25010G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251182

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135736

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Action myoclonus-renal failure syndrome

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2023	Variant summary: SCARB2 c.862C>T (p.Gln288X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251182 control chromosomes (gnomAD). c.862C>T has been reported in the literature in individuals affected with features of Action Myoclonus-Renal Failure Syndrome (examples: Berkovic_2008, and Li_2023). At least one publication reports experimental evidence that this variant disrupts the normal trafficking of the SCARB2 protein (Blanz_2010). The following publications have been ascertained in the context of this evaluation (PMID: 18308289, 19933215, 35478072). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 17, 2017

The Q288X nonsense variant in the SCARB2 gene has been reported previously in association with action myoclonus-renal failure syndrome and also progressive myoclonic epilepsy without renal failure (Berkovic et al., 2008; Dibbens et al., 2011). Functional analysis shows that Q288X disrupts the normal trafficking of the SCARB2 protein (Blanz et al., 2010). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Additionally, it was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, Q288X is interpreted to be a pathogenic variant. -

Progressive myoclonic epilepsy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

This sequence change creates a premature translational stop signal (p.Gln288*) 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 (rs121909118, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of SCARB2-related conditions (PMID: 18308289). ClinVar contains an entry for this variant (Variation ID: 7378). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.078

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.59

MutationTaster

Benign

1.0

A;A

Vest4

0.57

GERP RS

0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.43

Position offset: 37

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