chr4-76161917-TCAG-T

Variant names:

• chr4-76161917-TCAG-T
• rs3836573
• NM_005506.4:c.1399-169_1399-167delCTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_005506.4(SCARB2):​c.1399-169_1399-167delCTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 691,440 control chromosomes in the GnomAD database, including 37,294 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.36 (12799 hom., cov: 0)
  • Exomes 𝑓: 0.27 (24495 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.558
• 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 -10 ACMG points.

• BP6: Variant 4-76161917-TCAG-T is Benign according to our data. Variant chr4-76161917-TCAG-T is described in ClinVar as [Benign]. Clinvar id is 670900.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-169_1399-167delCTG		intron_variant	Intron 11 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-169_970-167delCTG		intron_variant	Intron 8 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.925-169_925-167delCTG		intron_variant	Intron 11 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.925-169_925-167delCTG		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.1399-169_1399-167delCTG		intron_variant	Intron 11 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54368 AN: 151448 Hom.: 12744 Cov.: 0

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.320

GnomAD4 exome AF: 0.271 AC: 146044 AN: 539874 Hom.: 24495 AF XY: 0.274 AC XY: 79354 AN XY: 289922

African (AFR) AF: 0.657 AC: 10151 AN: 15458

American (AMR) AF: 0.261 AC: 8682 AN: 33292

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 5108 AN: 17970

East Asian (EAS) AF: 0.618 AC: 19561 AN: 31634

South Asian (SAS) AF: 0.364 AC: 20873 AN: 57312

European-Finnish (FIN) AF: 0.255 AC: 8373 AN: 32884

Middle Eastern (MID) AF: 0.250 AC: 954 AN: 3812

European-Non Finnish (NFE) AF: 0.202 AC: 64095 AN: 317626

Other (OTH) AF: 0.276 AC: 8247 AN: 29886

GnomAD4 genome AF: 0.360 AC: 54493 AN: 151566 Hom.: 12799 Cov.: 0 AF XY: 0.362 AC XY: 26793 AN XY: 74058

African (AFR) AF: 0.658 AC: 27130 AN: 41204

American (AMR) AF: 0.258 AC: 3937 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 953 AN: 3472

East Asian (EAS) AF: 0.611 AC: 3107 AN: 5086

South Asian (SAS) AF: 0.378 AC: 1819 AN: 4808

European-Finnish (FIN) AF: 0.249 AC: 2622 AN: 10544

Middle Eastern (MID) AF: 0.255 AC: 74 AN: 290

European-Non Finnish (NFE) AF: 0.205 AC: 13904 AN: 67898

Other (OTH) AF: 0.325 AC: 683 AN: 2104

Alfa AF: 0.294 Hom.: 1063

Bravo AF: 0.373

Asia WGS AF: 0.532 AC: 1847 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 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
PhyloP100		0.56
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: rs3836573; hg19: chr4-77083070; COSMIC: COSV107295766;