rs147324129

Positions:

chr4-76169970-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005506.4(SCARB2):c.1010T>C(p.Met337Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

SCARB2
NM_005506.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: 8.26

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3632928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCARB2	NM_005506.4 linkuse as main transcript	c.1010T>C	p.Met337Thr	missense_variant	8/12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2 linkuse as main transcript	c.581T>C	p.Met194Thr	missense_variant	5/9		NP_001191184.1
SCARB2	XM_047416429.1 linkuse as main transcript	c.536T>C	p.Met179Thr	missense_variant	8/12		XP_047272385.1
SCARB2	XM_047416430.1 linkuse as main transcript	c.536T>C	p.Met179Thr	missense_variant	8/12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8 linkuse as main transcript	c.1010T>C	p.Met337Thr	missense_variant	8/12	1	NM_005506.4	ENSP00000264896	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.102+20704A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251216

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

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:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

151

AN:

1461532

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000201

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:

0.000118

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000666

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2024	Identified in a patient with epilepsy in published literature (PMID: 29358611); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358611) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Childhood epilepsy with centrotemporal spikes

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2018

The p.M337T variant (also known as c.1010T>C), located in coding exon 8 of the SCARB2 gene, results from a T to C substitution at nucleotide position 1010. The methionine at codon 337 is replaced by threonine, an amino acid with similar properties. This variant was detected in a cohort of individuals with Rolandic epilepsy; however, complete genotype and phenotype information was not provided (Bobbili DR et al. Eur. J. Hum. Genet., 2018 Feb;26:258-264). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Action myoclonus-renal failure syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 23, 2021

- -

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 09, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 337 of the SCARB2 protein (p.Met337Thr). This variant is present in population databases (rs147324129, gnomAD 0.01%). This missense change has been observed in individual(s) with Rolandic epilepsy (PMID: 29358611). ClinVar contains an entry for this variant (Variation ID: 206715). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

D;.;.;.;.;.;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D;D;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.36

T;T;T;T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

D;.;.;.;.;D;.

REVEL

Uncertain

0.46

Sift

Benign

0.030

D;.;.;.;.;D;.

Sift4G

Uncertain

0.041

D;.;.;.;.;D;.

Polyphen

0.16

B;.;.;.;.;.;.

Vest4

0.68

MVP

0.79

MPC

0.29

ClinPred

0.18

GERP RS

4.9

Varity_R

0.63

gMVP

0.72

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