rs149474488

chr4-76163361-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_005506.4(SCARB2):c.1262C>T(p.Thr421Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T421T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SCARB2 NM_005506.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.77

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14094993).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000199 (291/1461868) while in subpopulation EAS AF= 0.000655 (26/39698). AF 95% confidence interval is 0.000458. There are 1 homozygotes in gnomad4_exome. There are 147 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	UniProt
SCARB2	NM_005506.4	c.1262C>T	p.Thr421Met	missense_variant	11/12	ENST00000264896.8
SCARB2	NM_001204255.2	c.833C>T	p.Thr278Met	missense_variant	8/9
SCARB2	XM_047416429.1	c.788C>T	p.Thr263Met	missense_variant	11/12
SCARB2	XM_047416430.1	c.788C>T	p.Thr263Met	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCARB2	ENST00000264896.8	c.1262C>T	p.Thr421Met	missense_variant	11/12	1	NM_005506.4	P4
	ENST00000651366.1	n.102+14095G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251434 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135890

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000199 AC: 291 AN: 1461868 Hom.: 1 Cov.: 30 AF XY: 0.000202 AC XY: 147 AN XY: 727234

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74438

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 17, 2017	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2021

The c.1262C>T (p.T421M) alteration is located in exon 11 (coding exon 11) of the SCARB2 gene. This alteration results from a C to T substitution at nucleotide position 1262, causing the threonine (T) at amino acid position 421 to be replaced by a methionine (M). 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

Dec 21, 2021

- -

Progressive myoclonic epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 421 of the SCARB2 protein (p.Thr421Met). This variant is present in population databases (rs149474488, gnomAD 0.07%). 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: 206716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCARB2 protein function. 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	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;.;.;.;.;.
Eigen	Benign	0.085
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.;.
MutationTaster	Benign	0.57	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.3	N;.;.;.;.;.;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;.;.;.;D;.
Polyphen		0.99	D;.;.;.;.;.;.;.
Vest4		0.42
MVP		0.71
MPC		0.67
ClinPred		0.31	T
GERP RS		2.1
Varity_R		0.089
gMVP		0.61

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

Other links and lift over

dbSNP: rs149474488; hg19: chr4-77084514; COSMIC: COSV53668069;