rs149907021
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001122955.4(BSCL2):c.1145C>T(p.Ser382Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S382P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001122955.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BSCL2 | NM_001122955.4 | c.1145C>T | p.Ser382Leu | missense_variant | 9/11 | ENST00000360796.10 | |
HNRNPUL2-BSCL2 | NR_037946.1 | n.3665C>T | non_coding_transcript_exon_variant | 22/24 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BSCL2 | ENST00000360796.10 | c.1145C>T | p.Ser382Leu | missense_variant | 9/11 | 1 | NM_001122955.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000733 AC: 18AN: 245404Hom.: 0 AF XY: 0.0000977 AC XY: 13AN XY: 132998
GnomAD4 exome AF: 0.000166 AC: 242AN: 1461392Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 105AN XY: 726956
GnomAD4 genome ? AF: 0.0000459 AC: 7AN: 152354Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74504
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 28, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 23, 2023 | Variant summary: BSCL2 c.953C>T (p.Ser318Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 245404 control chromosomes (gnomAD). To our knowledge, no occurrence of c.953C>T in individuals affected with BSCL2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 02, 2021 | The p.S318L variant (also known as c.953C>T), located in coding exon 8 of the BSCL2 gene, results from a C to T substitution at nucleotide position 953. The serine at codon 318 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant BSCL2-related neurologic disorders; however, its contribution to the development of autosomal recessive BSCL2-related syndrome is uncertain. - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 08, 2020 | - - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 318 of the BSCL2 protein (p.Ser318Leu). This variant is present in population databases (rs149907021, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BSCL2-related conditions. ClinVar contains an entry for this variant (Variation ID: 411581). 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 BSCL2 protein function with a negative predictive value of 80%. 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. - |
Congenital generalized lipodystrophy type 2;C2931276:Hereditary spastic paraplegia 17;C4014700:Severe neurodegenerative syndrome with lipodystrophy;C5436838:Neuronopathy, distal hereditary motor, type 5C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 04, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at