NM_005506.4:c.1399-280C>T

Variant names:

• chr4-76162031-G-A
• rs72655526
• NM_005506.4:c.1399-280C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005506.4(SCARB2):​c.1399-280C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0465 in 507,224 control chromosomes in the GnomAD database, including 706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (184 hom., cov: 32)
  • Exomes 𝑓: 0.049 (522 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.178
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-76162031-G-A is Benign according to our data. Variant chr4-76162031-G-A is described in ClinVar as [Benign]. Clinvar id is 668971.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-280C>T		intron_variant	Intron 11 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-280C>T		intron_variant	Intron 8 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.925-280C>T		intron_variant	Intron 11 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.925-280C>T		intron_variant	Intron 11 of 11		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1399-280C>T		intron_variant	Intron 11 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6261 AN: 152096 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0411

GnomAD4 exome AF: 0.0488 AC: 17338 AN: 355010 Hom.: 522 Cov.: 0 AF XY: 0.0479 AC XY: 8972 AN XY: 187240

African (AFR) AF: 0.00907 AC: 95 AN: 10478

American (AMR) AF: 0.0318 AC: 503 AN: 15814

Ashkenazi Jewish (ASJ) AF: 0.00927 AC: 101 AN: 10894

East Asian (EAS) AF: 0.000171 AC: 4 AN: 23354

South Asian (SAS) AF: 0.0337 AC: 1378 AN: 40932

European-Finnish (FIN) AF: 0.0524 AC: 1059 AN: 20214

Middle Eastern (MID) AF: 0.0536 AC: 81 AN: 1512

European-Non Finnish (NFE) AF: 0.0620 AC: 13101 AN: 211274

Other (OTH) AF: 0.0495 AC: 1016 AN: 20538

GnomAD4 genome AF: 0.0411 AC: 6260 AN: 152214 Hom.: 184 Cov.: 32 AF XY: 0.0416 AC XY: 3097 AN XY: 74410

African (AFR) AF: 0.0109 AC: 454 AN: 41538

American (AMR) AF: 0.0374 AC: 572 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0300 AC: 145 AN: 4826

European-Finnish (FIN) AF: 0.0595 AC: 630 AN: 10584

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0613 AC: 4169 AN: 68010

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0447 Hom.: 59

Bravo AF: 0.0386

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.58
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72655526; hg19: chr4-77083184;