rs771661901

Variant names:

• chr4-76166254-T-A
• rs771661901
• NM_005506.4:c.1235A>T

Your query was ambiguous. Multiple possible variants found:

• chr4-76166254-T-A
• chr4-76166254-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005506.4(SCARB2):​c.1235A>T​(p.Asn412Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. N412S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SCARB2 NM_005506.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.93
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity SCRB2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCARB2	NM_005506.4	c.1235A>T	p.Asn412Ile	missense_variant	Exon 10 of 12	ENST00000264896.8	NP_005497.1
SCARB2	NM_001204255.2	c.806A>T	p.Asn269Ile	missense_variant	Exon 7 of 9		NP_001191184.1
SCARB2	XM_047416429.1	c.761A>T	p.Asn254Ile	missense_variant	Exon 10 of 12		XP_047272385.1
SCARB2	XM_047416430.1	c.761A>T	p.Asn254Ile	missense_variant	Exon 10 of 12		XP_047272386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCARB2	ENST00000264896.8	c.1235A>T	p.Asn412Ile	missense_variant	Exon 10 of 12	1	NM_005506.4	ENSP00000264896.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461540 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111704

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.5	H;.;.;.;.;.;.;.
PhyloP100		4.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.3	D;.;.;.;.;.;D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;D;.
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.87		Loss of catalytic residue at N412 (P = 0.0574);.;Loss of catalytic residue at N412 (P = 0.0574);.;.;.;.;Loss of catalytic residue at N412 (P = 0.0574);
MVP		0.85
MPC		0.96
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		0.0061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.90
Mutation Taster		=34/66	disease causing

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: rs771661901; hg19: chr4-77087407;