chr4-76161646-G-C

Variant names:

• chr4-76161646-G-C
• rs3733256
• NM_005506.4:c.*67C>G

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.*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
• Publications: 4 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=-0.87).
• 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 rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.*67C>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.*67C>G		3_prime_UTR_variant	Exon 9 of 9		NP_001191184.1
SCARB2	XM_047416429.1	c.*67C>G		3_prime_UTR_variant	Exon 12 of 12		XP_047272385.1
SCARB2	XM_047416430.1	c.*67C>G		3_prime_UTR_variant	Exon 12 of 12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.*67C>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_005506.4	ENSP00000264896.2

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

African (AFR) AF: 0.0745 AC: 2367 AN: 31758

American (AMR) AF: 0.00428 AC: 191 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 26 AN: 25680

East Asian (EAS) AF: 0.0488 AC: 1918 AN: 39326

South Asian (SAS) AF: 0.00296 AC: 250 AN: 84574

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53326

Middle Eastern (MID) AF: 0.00783 AC: 44 AN: 5622

European-Non Finnish (NFE) AF: 0.000761 AC: 790 AN: 1038114

Other (OTH) AF: 0.00852 AC: 491 AN: 57654

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

African (AFR) AF: 0.0715 AC: 2970 AN: 41510

American (AMR) AF: 0.00968 AC: 148 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.0507 AC: 262 AN: 5172

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.000850 AC: 9 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68018

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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	-0.87
CADD	Benign	0.83
DANN	Benign	0.50
PhyloP100		-0.072
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3733256; hg19: chr4-77082799;