rs2228380

Positions:

• chr4-76168404-C-A
• chr4-76168404-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005506.4(SCARB2):​c.1186G>T​(p.Val396Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V396I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCARB2 NM_005506.4 missense, splice_region
• Scores: Splicing: ADA: 0.00007015
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.333

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04769236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1186G>T	p.Val396Phe	missense_variant, splice_region_variant	9/12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.757G>T	p.Val253Phe	missense_variant, splice_region_variant	6/9		NP_001191184.1
SCARB2	XM_047416429.1	c.712G>T	p.Val238Phe	missense_variant, splice_region_variant	9/12		XP_047272385.1
SCARB2	XM_047416430.1	c.712G>T	p.Val238Phe	missense_variant, splice_region_variant	9/12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1186G>T	p.Val396Phe	missense_variant, splice_region_variant	9/12	1	NM_005506.4	ENSP00000264896	P4
	ENST00000651366.1	n.102+19138C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251368 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.49
DANN	Benign	0.22
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.048	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.74	N;.;.;.;.;N;.
REVEL	Benign	0.049
Sift	Benign	0.71	T;.;.;.;.;T;.
Sift4G	Benign	0.71	T;.;.;.;.;T;.
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.12
MutPred		0.38		Loss of sheet (P = 0.1158);.;Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);
MVP		0.16
MPC		0.32
ClinPred		0.017	T
GERP RS		-2.7
Varity_R		0.13
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.13		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: rs2228380; hg19: chr4-77089557;