chr9-92717947-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_001003800.2(BICD2):c.2108C>T(p.Thr703Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001003800.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BICD2 | NM_001003800.2 | c.2108C>T | p.Thr703Met | missense_variant, splice_region_variant | Exon 6 of 7 | ENST00000356884.11 | NP_001003800.1 | |
BICD2 | NM_015250.4 | c.2108C>T | p.Thr703Met | missense_variant, splice_region_variant | Exon 6 of 8 | NP_056065.1 | ||
BICD2 | XM_017014551.2 | c.2189C>T | p.Thr730Met | missense_variant, splice_region_variant | Exon 6 of 8 | XP_016870040.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BICD2 | ENST00000356884.11 | c.2108C>T | p.Thr703Met | missense_variant, splice_region_variant | Exon 6 of 7 | 1 | NM_001003800.2 | ENSP00000349351.6 | ||
BICD2 | ENST00000375512.3 | c.2108C>T | p.Thr703Met | missense_variant, splice_region_variant | Exon 6 of 8 | 1 | ENSP00000364662.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250388Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135396
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460538Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726622
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | not provided | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 06, 2013 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 17, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 703 of the BICD2 protein (p.Thr703Met). This variant is present in population databases (rs371707778, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of BICD2-related conditions (PMID: 23664116, 27784775, 28635954; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 55858). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116, 27784775, 29528393). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 14, 2025 | Published functional studies demonstrate a damaging effect: abnormal protein localization, increased Golgi fragmentation, and increased microtuble stability (PMID: 29528393, 23664116); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27784775, 33369814, 23664116, 28635954, 35982159, 34758253, 33057194, 29528393) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 02, 2023 | PP1, PS3, PS4_moderate - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 08, 2022 | The c.2108C>T (p.T703M) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution at nucleotide position 2108, causing the threonine (T) at amino acid position 703 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/281794) total alleles studied. The highest observed frequency was 0.004% (1/24960) of African alleles. This alteration was detected in multiple individuals with features consistent with lower extremity-predominant spinal muscular atrophy 2 (Storbeck, 2017; Unger, 2016; Neveling, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show aberrant protein function and mis-localization of protein in vitro and in vivo (Unger, 2016; Neveling, 2013; Martinez Carrera, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at