4-76161957-T-C

Variant names:

• chr4-76161957-T-C
• rs60271776
• NM_005506.4:c.1399-206A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005506.4(SCARB2):​c.1399-206A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 630,198 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: SCARB2 NM_005506.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.307
• Publications: 0 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=-0.88).
• BP6: Variant 4-76161957-T-C is Benign according to our data. Variant chr4-76161957-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1190487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00315 (479/152114) while in subpopulation AFR AF = 0.0109 (453/41476). AF 95% confidence interval is 0.0101. There are 3 homozygotes in GnomAd4. There are 227 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1399-206A>G		intron_variant	Intron 11 of 11	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.970-206A>G		intron_variant	Intron 8 of 8		NP_001191184.1
SCARB2	XM_047416429.1	c.925-206A>G		intron_variant	Intron 11 of 11		XP_047272385.1
SCARB2	XM_047416430.1	c.925-206A>G		intron_variant	Intron 11 of 11		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1399-206A>G		intron_variant	Intron 11 of 11	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 478 AN: 151996 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000427 AC: 204 AN: 478084 Hom.: 2 Cov.: 0 AF XY: 0.000330 AC XY: 84 AN XY: 254736

African (AFR) AF: 0.0122 AC: 168 AN: 13816

American (AMR) AF: 0.000437 AC: 12 AN: 27478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15118

East Asian (EAS) AF: 0.00 AC: 0 AN: 30898

South Asian (SAS) AF: 0.0000198 AC: 1 AN: 50508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29924

Middle Eastern (MID) AF: 0.000757 AC: 2 AN: 2642

European-Non Finnish (NFE) AF: 0.00000713 AC: 2 AN: 280508

Other (OTH) AF: 0.000699 AC: 19 AN: 27192

GnomAD4 genome AF: 0.00315 AC: 479 AN: 152114 Hom.: 3 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74372

African (AFR) AF: 0.0109 AC: 453 AN: 41476

American (AMR) AF: 0.00111 AC: 17 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00222 Hom.: 1

Bravo AF: 0.00353

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Likely 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	-0.88
CADD	Benign	3.5
DANN	Benign	0.86
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism

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: rs60271776; hg19: chr4-77083110;