9-92715401-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_001003800.2(BICD2):c.2321A>G(p.Glu774Gly) 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. 13/21 in silico tools predict a damaging 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. E774K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001003800.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BICD2 | NM_001003800.2 | c.2321A>G | p.Glu774Gly | missense_variant | 7/7 | ENST00000356884.11 | |
BICD2 | NM_015250.4 | c.2321A>G | p.Glu774Gly | missense_variant | 7/8 | ||
BICD2 | XM_017014551.2 | c.2402A>G | p.Glu801Gly | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BICD2 | ENST00000356884.11 | c.2321A>G | p.Glu774Gly | missense_variant | 7/7 | 1 | NM_001003800.2 | A2 | |
BICD2 | ENST00000375512.3 | c.2321A>G | p.Glu774Gly | missense_variant | 7/8 | 1 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 06, 2013 | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2016 | The E774K variant in the BICD2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a missense variant at this same codon (E774G) has been reported as a de novo variant in an individual with spinal muscular atrophy (Peeters et al., 2013). The E774K variant is not observed in large population cohorts (Lek et al., 2016). The E774K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret E774K as a pathogenic variant - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at