chr4-76181100-C-T

Position:

chr4-76181100-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_005506.4(SCARB2):c.277G>A(p.Glu93Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000182 in 1,613,272 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

SCARB2
NM_005506.4 missense, splice_region

Scores

Splicing: ADA: 0.9926

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 6.61

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;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000183 (268/1461000) while in subpopulation MID AF= 0.00384 (22/5736). AF 95% confidence interval is 0.0026. There are 1 homozygotes in gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SCARB2	NM_005506.4 linkuse as main transcript	c.277G>A	p.Glu93Lys	missense_variant, splice_region_variant	3/12	ENST00000264896.8	NP_005497.1
SCARB2	XM_047416429.1 linkuse as main transcript	c.-198G>A		splice_region_variant, 5_prime_UTR_variant	3/12		XP_047272385.1
SCARB2	XM_047416430.1 linkuse as main transcript	c.-198G>A		splice_region_variant, 5_prime_UTR_variant	3/12		XP_047272386.1
SCARB2	NM_001204255.2 linkuse as main transcript	c.276-5190G>A		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.277G>A	p.Glu93Lys	missense_variant, splice_region_variant	3/12	1	NM_005506.4	ENSP00000264896	P4	Q14108-1
	ENST00000651366.1 linkuse as main transcript	n.103-18866C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

250754

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000183

AC:

268

AN:

1461000

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000189

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000171

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in the heterozgyous state in a patient with focal epilepsy and SUDEP, who also harbored rare variants in five other genes; segregation was inconclusive (Coll et al., 2017); This variant is associated with the following publications: (PMID: 29261713, 34791078) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 01, 2017

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

The c.277G>A (p.E93K) alteration is located in exon 3 (coding exon 3) of the SCARB2 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the glutamic acid (E) at amino acid position 93 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, 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

Apr 16, 2022

- -

Progressive myoclonic epilepsy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 93 of the SCARB2 protein (p.Glu93Lys). This variant is present in population databases (rs145870223, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with focal epilepsy and sudden unexpected death in epilepsy (SUDEP) (PMID: 29261713). ClinVar contains an entry for this variant (Variation ID: 206724). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). 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

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.0

D;.;.;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0080

D;.;.;.

Sift4G

Uncertain

0.019

D;.;.;.

Polyphen

0.98

D;.;.;.

Vest4

0.93

MVP

0.90

MPC

0.71

ClinPred

0.39

GERP RS

5.7

Varity_R

0.88

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.88

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