rs774721226

chr4-76213511-C-Achr4-76213511-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM2 BP4 BP6_Very_Strong BP7 BS1

The NM_005506.4(SCARB2):c.33G>T(p.Thr11=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,610,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SCARB2 NM_005506.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.425

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.14).
• BP6: Variant 4-76213511-C-A is Benign according to our data. Variant chr4-76213511-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 259782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000161 (235/1457928) while in subpopulation SAS AF= 0.00159 (136/85482). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCARB2	NM_005506.4	c.33G>T	p.Thr11=	synonymous_variant	1/12	ENST00000264896.8
SCARB2	NM_001204255.2	c.33G>T	p.Thr11=	synonymous_variant	1/9
SCARB2	XM_047416429.1	c.-357-17647G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCARB2	ENST00000264896.8	c.33G>T	p.Thr11=	synonymous_variant	1/12	1	NM_005506.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000253 AC: 60 AN: 236698 Hom.: 0 AF XY: 0.000326 AC XY: 42 AN XY: 128704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000851

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1457928 Hom.: 0 Cov.: 30 AF XY: 0.000192 AC XY: 139 AN XY: 724878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00159

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152254 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Action myoclonus-renal failure syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Progressive myoclonic epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.14
Cadd	Benign	11
Dann	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs774721226; hg19: chr4-77134664;