4-76161929-A-T

Position:

• chr4-76161929-A-T

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.1399-178T>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

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=-0.79).
• 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/exons	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-178T>A		intron_variant		ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-178T>A		intron_variant			NP_001191184.1
SCARB2	XM_047416429.1	c.925-178T>A		intron_variant			XP_047272385.1
SCARB2	XM_047416430.1	c.925-178T>A		intron_variant			XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1399-178T>A		intron_variant		1	NM_005506.4	ENSP00000264896	P4
	ENST00000651366.1	n.102+12663A>T		intron_variant, non_coding_transcript_variant

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

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.236

Gnomad4 SAS exome AF: 0.199

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.0574

Gnomad4 OTH exome AF: 0.0960

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

Gnomad4 AFR AF: 0.184

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.211

Gnomad4 SAS AF: 0.193

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0583

Gnomad4 OTH AF: 0.0943

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.5
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs3755890; hg19: chr4-77083082;