rs143655258

chr4-76179654-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005506.4(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 NM_005506.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.140

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 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCARB2	NM_005506.4	c.475A>G	p.Met159Val	missense_variant	4/12	ENST00000264896.8
SCARB2	XM_047416429.1	c.1A>G	p.Met1?	start_lost	4/12
SCARB2	XM_047416430.1	c.1A>G	p.Met1?	start_lost	4/12
SCARB2	NM_001204255.2	c.276-3744A>G		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00837 AC: 1274 AN: 152218 Hom.: 8 Cov.: 33

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.: 18 AF XY: 0.00872 AC XY: 1185 AN XY: 135822

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.: 90 Cov.: 31 AF XY: 0.00936 AC XY: 6810 AN XY: 727186

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.: 8 Cov.: 33 AF XY: 0.00824 AC XY: 614 AN XY: 74484

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.: 24

Bravo AF: 0.00824

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.00896 AC: 1088

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ENSG00000286074: BS1, BS2; SCARB2: BP4, BS1, BS2 -
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

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.59	T
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	N
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	T
MutationAssessor	Benign	0.98	L;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs143655258; hg19: chr4-77100807;