rs149474488
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The ENST00000264896.8(SCARB2):c.1262C>T(p.Thr421Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,614,144 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T421T) has been classified as Likely benign.
Frequency
Consequence
ENST00000264896.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCARB2 | NM_005506.4 | c.1262C>T | p.Thr421Met | missense_variant | 11/12 | ENST00000264896.8 | NP_005497.1 | |
SCARB2 | NM_001204255.2 | c.833C>T | p.Thr278Met | missense_variant | 8/9 | NP_001191184.1 | ||
SCARB2 | XM_047416429.1 | c.788C>T | p.Thr263Met | missense_variant | 11/12 | XP_047272385.1 | ||
SCARB2 | XM_047416430.1 | c.788C>T | p.Thr263Met | missense_variant | 11/12 | XP_047272386.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCARB2 | ENST00000264896.8 | c.1262C>T | p.Thr421Met | missense_variant | 11/12 | 1 | NM_005506.4 | ENSP00000264896 | P4 | |
ENST00000651366.1 | n.102+14095G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000235 AC: 59AN: 251434Hom.: 0 AF XY: 0.000191 AC XY: 26AN XY: 135890
GnomAD4 exome AF: 0.000199 AC: 291AN: 1461868Hom.: 1 Cov.: 30 AF XY: 0.000202 AC XY: 147AN XY: 727234
GnomAD4 genome AF: 0.000131 AC: 20AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74438
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 28, 2024 | Reported previously as a variant of uncertain significance in three patients with Parkinson's disease and one control sample; however, no further clinical or segregation information was provided (PMID: 34867278); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34867278) - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 30, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 17, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2021 | The c.1262C>T (p.T421M) alteration is located in exon 11 (coding exon 11) of the SCARB2 gene. This alteration results from a C to T substitution at nucleotide position 1262, causing the threonine (T) at amino acid position 421 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Action myoclonus-renal failure syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 21, 2021 | - - |
Progressive myoclonic epilepsy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 421 of the SCARB2 protein (p.Thr421Met). This variant is present in population databases (rs149474488, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SCARB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 206716). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SCARB2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at