4-76169853-A-T

Variant names:

• chr4-76169853-A-T
• rs35369082
• NM_005506.4:c.1113+14T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005506.4(SCARB2):​c.1113+14T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,557,634 control chromosomes in the GnomAD database, including 22,535 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3622 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18913 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46
• Publications: 7 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:58820):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-76169853-A-T is Benign according to our data. Variant chr4-76169853-A-T is described in ClinVar as Benign. ClinVar VariationId is 138968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1113+14T>A		intron_variant	Intron 8 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.684+14T>A		intron_variant	Intron 5 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.639+14T>A		intron_variant	Intron 8 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.639+14T>A		intron_variant	Intron 8 of 11		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1113+14T>A		intron_variant	Intron 8 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30913 AN: 152020 Hom.: 3607 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.190

GnomAD2 exomes AF: 0.177 AC: 44539 AN: 251288 AF XY: 0.174

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.349

Gnomad FIN exome AF: 0.136

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.157 AC: 220068 AN: 1405496 Hom.: 18913 Cov.: 24 AF XY: 0.157 AC XY: 110478 AN XY: 702776

African (AFR) AF: 0.321 AC: 10334 AN: 32190

American (AMR) AF: 0.150 AC: 6715 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4372 AN: 25762

East Asian (EAS) AF: 0.341 AC: 13414 AN: 39374

South Asian (SAS) AF: 0.167 AC: 14172 AN: 85116

European-Finnish (FIN) AF: 0.134 AC: 7163 AN: 53336

Middle Eastern (MID) AF: 0.131 AC: 741 AN: 5638

European-Non Finnish (NFE) AF: 0.145 AC: 153528 AN: 1060910

Other (OTH) AF: 0.165 AC: 9629 AN: 58508

GnomAD4 genome AF: 0.203 AC: 30950 AN: 152138 Hom.: 3622 Cov.: 32 AF XY: 0.203 AC XY: 15081 AN XY: 74364

African (AFR) AF: 0.318 AC: 13183 AN: 41482

American (AMR) AF: 0.160 AC: 2446 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 581 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1815 AN: 5164

South Asian (SAS) AF: 0.179 AC: 864 AN: 4828

European-Finnish (FIN) AF: 0.139 AC: 1473 AN: 10586

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9908 AN: 68016

Other (OTH) AF: 0.192 AC: 405 AN: 2114

Alfa AF: 0.103 Hom.: 195

Bravo AF: 0.210

Asia WGS AF: 0.253 AC: 879 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 11, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive myoclonic epilepsy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs35369082; hg19: chr4-77091006; COSMIC: COSV53669929; COSMIC: COSV53669929;