4-76174062-C-T

Variant names:

• chr4-76174062-C-T
• rs41284767
• NM_005506.4:c.994+82G>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.994+82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,545,008 control chromosomes in the GnomAD database, including 24,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4677 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19434 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.33
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 4-76174062-C-T is Benign according to our data. Variant chr4-76174062-C-T is described in ClinVar as Benign. ClinVar VariationId is 1178406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.994+82G>A		intron_variant	Intron 7 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.565+82G>A		intron_variant	Intron 4 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.520+82G>A		intron_variant	Intron 7 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.520+82G>A		intron_variant	Intron 7 of 11		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.994+82G>A		intron_variant	Intron 7 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34012 AN: 151874 Hom.: 4659 Cov.: 32

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.158 AC: 220055 AN: 1393018 Hom.: 19434 Cov.: 22 AF XY: 0.159 AC XY: 110505 AN XY: 696560

African (AFR) AF: 0.391 AC: 12415 AN: 31734

American (AMR) AF: 0.155 AC: 6885 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4329 AN: 25576

East Asian (EAS) AF: 0.339 AC: 13335 AN: 39296

South Asian (SAS) AF: 0.174 AC: 14618 AN: 84138

European-Finnish (FIN) AF: 0.134 AC: 7106 AN: 53022

Middle Eastern (MID) AF: 0.138 AC: 555 AN: 4032

European-Non Finnish (NFE) AF: 0.143 AC: 151024 AN: 1052648

Other (OTH) AF: 0.169 AC: 9788 AN: 58012

GnomAD4 genome AF: 0.224 AC: 34053 AN: 151990 Hom.: 4677 Cov.: 32 AF XY: 0.223 AC XY: 16568 AN XY: 74288

African (AFR) AF: 0.388 AC: 16094 AN: 41430

American (AMR) AF: 0.167 AC: 2550 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3468

East Asian (EAS) AF: 0.351 AC: 1812 AN: 5156

South Asian (SAS) AF: 0.187 AC: 898 AN: 4810

European-Finnish (FIN) AF: 0.139 AC: 1470 AN: 10562

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.146 AC: 9927 AN: 67980

Other (OTH) AF: 0.211 AC: 446 AN: 2112

Alfa AF: 0.191 Hom.: 447

Bravo AF: 0.234

Asia WGS AF: 0.263 AC: 911 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 25, 2018

GeneDx

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	-1.0
CADD	Benign	1.6
DANN	Benign	0.74
PhyloP100		-1.3
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: rs41284767; hg19: chr4-77095215; COSMIC: COSV53669935; COSMIC: COSV53669935;