chr4-76161929-A-T

Variant names:

• chr4-76161929-A-T
• rs3755890
• NM_005506.4:c.1399-178T>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.1399-178T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 669,840 control chromosomes in the GnomAD database, including 4,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1117 hom., cov: 32)
  • Exomes 𝑓: 0.099 (3636 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.322
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 4-76161929-A-T is Benign according to our data. Variant chr4-76161929-A-T is described in ClinVar as [Benign]. Clinvar id is 1236617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-178T>A		intron_variant	Intron 11 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-178T>A		intron_variant	Intron 8 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.925-178T>A		intron_variant	Intron 11 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.925-178T>A		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.1399-178T>A		intron_variant	Intron 11 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16531 AN: 151654 Hom.: 1099 Cov.: 32

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0806

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0583

Gnomad OTH AF: 0.0915

GnomAD4 exome AF: 0.0987 AC: 51159 AN: 518068 Hom.: 3636 Cov.: 5 AF XY: 0.104 AC XY: 28867 AN XY: 277690

African (AFR) AF: 0.192 AC: 2893 AN: 15078

American (AMR) AF: 0.104 AC: 3359 AN: 32200

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 1966 AN: 17072

East Asian (EAS) AF: 0.236 AC: 7424 AN: 31416

South Asian (SAS) AF: 0.199 AC: 10989 AN: 55218

European-Finnish (FIN) AF: 0.124 AC: 3982 AN: 32008

Middle Eastern (MID) AF: 0.111 AC: 397 AN: 3590

European-Non Finnish (NFE) AF: 0.0574 AC: 17366 AN: 302484

Other (OTH) AF: 0.0960 AC: 2783 AN: 29002

GnomAD4 genome AF: 0.109 AC: 16604 AN: 151772 Hom.: 1117 Cov.: 32 AF XY: 0.113 AC XY: 8409 AN XY: 74192

African (AFR) AF: 0.184 AC: 7601 AN: 41266

American (AMR) AF: 0.0814 AC: 1242 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3470

East Asian (EAS) AF: 0.211 AC: 1084 AN: 5146

South Asian (SAS) AF: 0.193 AC: 926 AN: 4792

European-Finnish (FIN) AF: 0.109 AC: 1156 AN: 10570

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0583 AC: 3964 AN: 67952

Other (OTH) AF: 0.0943 AC: 199 AN: 2110

Alfa AF: 0.0361 Hom.: 32

Bravo AF: 0.108

Asia WGS AF: 0.254 AC: 882 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 23, 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	-0.79
CADD	Benign	7.5
DANN	Benign	0.74
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3755890; hg19: chr4-77083082;