11-62702493-G-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_ModeratePP5_Moderate
The NM_001122955.4(BSCL2):c.461C>G(p.Ser154Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S154L) has been classified as Pathogenic.
Frequency
Consequence
NM_001122955.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BSCL2 | NM_001122955.4 | c.461C>G | p.Ser154Trp | missense_variant | Exon 3 of 11 | ENST00000360796.10 | NP_001116427.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BSCL2 | ENST00000360796.10 | c.461C>G | p.Ser154Trp | missense_variant | Exon 3 of 11 | 1 | NM_001122955.4 | ENSP00000354032.5 | ||
HNRNPUL2-BSCL2 | ENST00000403734.2 | n.*512C>G | non_coding_transcript_exon_variant | Exon 16 of 24 | 2 | ENSP00000456010.1 | ||||
HNRNPUL2-BSCL2 | ENST00000403734.2 | n.*512C>G | 3_prime_UTR_variant | Exon 16 of 24 | 2 | ENSP00000456010.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser90 amino acid residue in BSCL2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17387721, 17486577, 20806400, 21957196, 24604904, 25487175, 26815532, 27549087). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt BSCL2 protein function. ClinVar contains an entry for this variant (Variation ID: 476810). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease type 2 (PMID: 23142943). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the BSCL2 protein (p.Ser90Trp). -
Neuronopathy, distal hereditary motor, type 5C Pathogenic:1
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Charcot-Marie-Tooth disease Uncertain:1
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Berardinelli-Seip congenital lipodystrophy Uncertain:1
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Hereditary spastic paraplegia 17 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at