4-76179654-T-C

Position:

chr4-76179654-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000264896.8(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. 15/20 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
ENST00000264896.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.140

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 Benign. Variant got -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 id is 206702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-76179654-T-C is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCARB2	NM_005506.4 linkuse as main transcript	c.475A>G	p.Met159Val	missense_variant	4/12	ENST00000264896.8	NP_005497.1
SCARB2	XM_047416429.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	4/12		XP_047272385.1
SCARB2	XM_047416430.1 linkuse as main transcript	c.1A>G	p.Met1?	start_lost	4/12		XP_047272386.1
SCARB2	NM_001204255.2 linkuse as main transcript	c.276-3744A>G		intron_variant			NP_001191184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8 linkuse as main transcript	c.475A>G	p.Met159Val	missense_variant	4/12	1	NM_005506.4	ENSP00000264896	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.103-20312T>C		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.00861

AC:

2163

AN:

251304

Hom.:

AF XY:

0.00872

AC XY:

1185

AN XY:

135822

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 SAS exome

AF:

0.000817

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

Gnomad4 AFR exome

AF:

0.00239

Gnomad4 AMR exome

AF:

0.00807

Gnomad4 ASJ exome

AF:

0.0132

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0104

GnomAD4 genome

AF:

0.00836

AC:

1273

AN:

152336

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

614

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00908

Gnomad4 ASJ

AF:

0.0133

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00932

Gnomad4 NFE

AF:

0.0126

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0110

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

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	SCARB2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2018	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2017

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. -

Action myoclonus-renal failure syndrome

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 13, 2021

- -

Progressive myoclonic epilepsy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.8

DANN

Benign

0.56

DEOGEN2

Benign

0.12

T;.;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.64

T;D;T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.98

L;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.43

N;.;.;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.45

T;.;.;.;.;.

Sift4G

Benign

0.31

T;.;.;.;.;.

Polyphen

0.0

B;.;.;.;.;.

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

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

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