4-76161646-G-C

Position:

• chr4-76161646-G-C

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.*67C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0063 in 1,532,894 control chromosomes in the GnomAD database, including 250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (107 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (143 hom.)
• Consequence: SCARB2 NM_005506.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0720

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=-0.87).
• BP6: Variant 4-76161646-G-C is Benign according to our data. Variant chr4-76161646-G-C is described in ClinVar as [Benign]. Clinvar id is 1224708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.*67C>G		3_prime_UTR_variant	12/12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.*67C>G		3_prime_UTR_variant	9/9		NP_001191184.1
SCARB2	XM_047416429.1	c.*67C>G		3_prime_UTR_variant	12/12		XP_047272385.1
SCARB2	XM_047416430.1	c.*67C>G		3_prime_UTR_variant	12/12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.*67C>G		3_prime_UTR_variant	12/12	1	NM_005506.4	ENSP00000264896	P4
	ENST00000651366.1	n.102+12380G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3527 AN: 152082 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0505

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.00443 AC: 6118 AN: 1380694 Hom.: 143 Cov.: 23 AF XY: 0.00425 AC XY: 2937 AN XY: 691498

Gnomad4 AFR exome AF: 0.0745

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.0488

Gnomad4 SAS exome AF: 0.00296

Gnomad4 FIN exome AF: 0.000769

Gnomad4 NFE exome AF: 0.000761

Gnomad4 OTH exome AF: 0.00852

GnomAD4 genome AF: 0.0233 AC: 3539 AN: 152200 Hom.: 107 Cov.: 32 AF XY: 0.0229 AC XY: 1708 AN XY: 74424

Gnomad4 AFR AF: 0.0715

Gnomad4 AMR AF: 0.00968

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0507

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0154 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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.83
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3733256; hg19: chr4-77082799;