9-92715324-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2

The NM_001003800.2(BICD2):ā€‹c.2398G>Cā€‹(p.Glu800Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

BICD2
NM_001003800.2 missense

Scores

4
9
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.82
Variant links:
Genes affected
BICD2 (HGNC:17208): (BICD cargo adaptor 2) This gene is one of two human homologs of Drosophila bicaudal-D and a member of the Bicoid family. It has been implicated in dynein-mediated, minus end-directed motility along microtubules. It has also been reported to be a phosphorylation target of NIMA related kinase 8. Two alternative splice variants have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1
In a coiled_coil_region (size 142) in uniprot entity BICD2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001003800.2
PP3
MetaRNN computational evidence supports a deleterious effect, 0.827
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BICD2NM_001003800.2 linkc.2398G>C p.Glu800Gln missense_variant Exon 7 of 7 ENST00000356884.11 NP_001003800.1 Q8TD16-2Q96FU2
BICD2NM_015250.4 linkc.2398G>C p.Glu800Gln missense_variant Exon 7 of 8 NP_056065.1 Q8TD16-1Q96FU2
BICD2XM_017014551.2 linkc.2479G>C p.Glu827Gln missense_variant Exon 7 of 8 XP_016870040.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BICD2ENST00000356884.11 linkc.2398G>C p.Glu800Gln missense_variant Exon 7 of 7 1 NM_001003800.2 ENSP00000349351.6 Q8TD16-2
BICD2ENST00000375512.3 linkc.2398G>C p.Glu800Gln missense_variant Exon 7 of 8 1 ENSP00000364662.3 Q8TD16-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460552
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726624
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 11, 2020The p.E800Q variant (also known as c.2398G>C), located in coding exon 7 of the BICD2 gene, results from a G to C substitution at nucleotide position 2398. The glutamic acid at codon 800 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 05, 2022This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 800 of the BICD2 protein (p.Glu800Gln). This variant is not present in population databases (gnomAD no frequency). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BICD2 protein function. This variant has not been reported in the literature in individuals affected with BICD2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
.;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Pathogenic
3.4
M;M
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.5
D;D
REVEL
Benign
0.27
Sift
Benign
0.053
T;T
Sift4G
Uncertain
0.0090
D;D
Polyphen
1.0
D;D
Vest4
0.70
MutPred
0.63
Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);
MVP
0.92
MPC
1.5
ClinPred
0.97
D
GERP RS
5.3
Varity_R
0.56
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1273239213; hg19: chr9-95477606; COSMIC: COSV105276233; API