NM_005506.4:c.1412A>T

Variant names:

• chr4-76161738-T-A
• rs755903502
• NM_005506.4:c.1412A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005506.4(SCARB2):​c.1412A>T​(p.Glu471Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,872 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E471G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SCARB2 NM_005506.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.82
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• action myoclonus-renal failure syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• progressive myoclonus epilepsy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000286074 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24259216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1412A>T	p.Glu471Val	missense_variant	Exon 12 of 12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.983A>T	p.Glu328Val	missense_variant	Exon 9 of 9		NP_001191184.1
SCARB2	XM_047416429.1	c.938A>T	p.Glu313Val	missense_variant	Exon 12 of 12		XP_047272385.1
SCARB2	XM_047416430.1	c.938A>T	p.Glu313Val	missense_variant	Exon 12 of 12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1412A>T	p.Glu471Val	missense_variant	Exon 12 of 12	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250596 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Action myoclonus-renal failure syndrome Uncertain:1

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 29, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Progressive myoclonic epilepsy Uncertain:1

Dec 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 471 of the SCARB2 protein (p.Glu471Val). This variant is present in population databases (rs755903502, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCARB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 582195). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	0.65
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.;.
PhyloP100		3.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.;D
REVEL	Uncertain	0.60
Sift	Benign	0.082	T;.;.;.;.;T
Sift4G	Uncertain	0.0070	D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;.;.
Vest4		0.54
MutPred		0.40		Loss of disorder (P = 0.0015);.;.;.;.;.;
MVP		0.86
MPC		0.43
ClinPred		0.15	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.78
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs755903502; hg19: chr4-77082891;