chr4-76161747-G-A

Position:

chr4-76161747-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005506.4(SCARB2):c.1403C>T(p.Thr468Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SCARB2
NM_005506.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.26

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SCARB2	NM_005506.4 linkuse as main transcript	c.1403C>T	p.Thr468Ile	missense_variant	12/12	ENST00000264896.8
SCARB2	NM_001204255.2 linkuse as main transcript	c.974C>T	p.Thr325Ile	missense_variant	9/9
SCARB2	XM_047416429.1 linkuse as main transcript	c.929C>T	p.Thr310Ile	missense_variant	12/12
SCARB2	XM_047416430.1 linkuse as main transcript	c.929C>T	p.Thr310Ile	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCARB2	ENST00000264896.8 linkuse as main transcript	c.1403C>T	p.Thr468Ile	missense_variant	12/12	1	NM_005506.4	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.102+12481G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152170

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

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727238

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

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: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.1403C>T (p.T468I) alteration is located in exon 12 (coding exon 12) of the SCARB2 gene. This alteration results from a C to T substitution at nucleotide position 1403, causing the threonine (T) at amino acid position 468 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2014

p.Thr468Ile (ACA>ATA): c.1403 C>T in exon 12 of the SCARB2 gene (NM_005506.3) A variant of unknown significance has been identified in the SCARB2 gene. The T468I variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. 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. The T468I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether the T468I variant is a pathogenic mutation or a rare benign variant.The variant is found in EPILEPSY panel(s). -

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.;.;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

D;D;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.50

D;D;D;D;D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Benign

2.0

M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.0

N;.;.;.;.;N

REVEL

Uncertain

0.44

Sift

Uncertain

0.0070

D;.;.;.;.;D

Sift4G

Uncertain

0.012

D;.;.;.;.;D

Polyphen

0.96

D;.;.;.;.;.

Vest4

0.34

MVP

0.87

MPC

0.45

ClinPred

0.80

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.060

gMVP

0.64

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