4-76162031-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
SCARB2	NM_005506.4	c.1399-280C>T		intron_variant		ENST00000264896.8
SCARB2	NM_001204255.2	c.970-280C>T		intron_variant
SCARB2	XM_047416429.1	c.925-280C>T		intron_variant
SCARB2	XM_047416430.1	c.925-280C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCARB2	ENST00000264896.8	c.1399-280C>T		intron_variant		1	NM_005506.4	P4
	ENST00000651366.1	n.102+12765G>A		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.00907

Gnomad4 AMR exome AF: 0.0318

Gnomad4 ASJ exome AF: 0.00927

Gnomad4 EAS exome AF: 0.000171

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.0620

Gnomad4 OTH exome AF: 0.0495

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

Gnomad4 AFR AF: 0.0109

Gnomad4 AMR AF: 0.0374

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0300

Gnomad4 FIN AF: 0.0595

Gnomad4 NFE AF: 0.0613

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0492 Hom.: 31

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs72655526; hg19: chr4-77083184;