4-76161971-C-A

Position:

• chr4-76161971-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005506.4(SCARB2):​c.1399-220G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 612,698 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (76 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.227

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-76161971-C-A is Benign according to our data. Variant chr4-76161971-C-A is described in ClinVar as [Benign]. Clinvar id is 673157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-220G>T		intron_variant		ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-220G>T		intron_variant			NP_001191184.1
SCARB2	XM_047416429.1	c.925-220G>T		intron_variant			XP_047272385.1
SCARB2	XM_047416430.1	c.925-220G>T		intron_variant			XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1399-220G>T		intron_variant		1	NM_005506.4	ENSP00000264896	P4
	ENST00000651366.1	n.102+12705C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3516 AN: 152044 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0714

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0186

GnomAD4 exome AF: 0.00691 AC: 3182 AN: 460536 Hom.: 76 Cov.: 0 AF XY: 0.00631 AC XY: 1549 AN XY: 245364

Gnomad4 AFR exome AF: 0.0696

Gnomad4 AMR exome AF: 0.00484

Gnomad4 ASJ exome AF: 0.00140

Gnomad4 EAS exome AF: 0.0462

Gnomad4 SAS exome AF: 0.00305

Gnomad4 FIN exome AF: 0.000763

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.0232 AC: 3528 AN: 152162 Hom.: 109 Cov.: 32 AF XY: 0.0229 AC XY: 1704 AN XY: 74402

Gnomad4 AFR AF: 0.0714

Gnomad4 AMR AF: 0.00955

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0506

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.000849

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0164 Hom.: 11

Bravo AF: 0.0264

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 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	-0.82
CADD	Benign	2.6
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs75945181; hg19: chr4-77083124;