rs1064795760
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_001003800.2(BICD2):c.1636_1638delAAT(p.Asn546del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001003800.2 conservative_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BICD2 | NM_001003800.2 | c.1636_1638delAAT | p.Asn546del | conservative_inframe_deletion | Exon 5 of 7 | ENST00000356884.11 | NP_001003800.1 | |
BICD2 | NM_015250.4 | c.1636_1638delAAT | p.Asn546del | conservative_inframe_deletion | Exon 5 of 8 | NP_056065.1 | ||
BICD2 | XM_017014551.2 | c.1717_1719delAAT | p.Asn573del | conservative_inframe_deletion | Exon 5 of 8 | XP_016870040.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BICD2 | ENST00000356884.11 | c.1636_1638delAAT | p.Asn546del | conservative_inframe_deletion | Exon 5 of 7 | 1 | NM_001003800.2 | ENSP00000349351.6 | ||
BICD2 | ENST00000375512.3 | c.1636_1638delAAT | p.Asn546del | conservative_inframe_deletion | Exon 5 of 8 | 1 | ENSP00000364662.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
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not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33547725, 30054298) -
Recurrent fractures;C0036572:Seizure;C0151611:EEG abnormality;C0151786:Muscle weakness;C0232466:Feeding difficulties;C0235659:Decreased fetal movement;C0240379:Open mouth;C0426886:Tapered finger;C0541794:Muscular atrophy;C1854882:Absent speech;C1866195:Downturned corners of mouth;C2243051:Macrocephaly;C4551583:Cerebral cortical atrophy;C5779613:Arthrogryposis multiplex congenita Pathogenic:1
The c.1636_1638delAAT variant results in an in-frame 3 base pair deletion and is predicted to cause loss of an evolutionarily conserved Asparagine residue in a non-repetitive region of the protein (p.Asn546del). It has not been reported in large population cohorts such as gnomAD. In silico modeling suggests that removing the Asn546 disrupts protein secondary structure in a region that has been shown (in mice) to bind KIF5A. This mutation occurred de novo in our patient and was reported by GeneDx in an unrelated patient who shared similar features. We therefore interpret the variant as likely pathogenic. -
Spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at