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

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BICD2
NM_001003800.2 missense, splice_region

Scores

12
6
1
Splicing: ADA: 0.9769
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 9.89
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
PP5
Variant 9-92717947-G-A is Pathogenic according to our data. Variant chr9-92717947-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92717947-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BICD2NM_001003800.2 linkc.2108C>T p.Thr703Met missense_variant, splice_region_variant Exon 6 of 7 ENST00000356884.11 NP_001003800.1 Q8TD16-2Q96FU2
BICD2NM_015250.4 linkc.2108C>T p.Thr703Met missense_variant, splice_region_variant Exon 6 of 8 NP_056065.1 Q8TD16-1Q96FU2
BICD2XM_017014551.2 linkc.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
BICD2ENST00000356884.11 linkc.2108C>T p.Thr703Met missense_variant, splice_region_variant Exon 6 of 7 1 NM_001003800.2 ENSP00000349351.6 Q8TD16-2
BICD2ENST00000375512.3 linkc.2108C>T p.Thr703Met missense_variant, splice_region_variant Exon 6 of 8 1 ENSP00000364662.3 Q8TD16-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250388
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135396
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460538
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726622
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152228
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000526
Hom.:
0
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitternot providedInstitute of Human Genetics, University Hospital of Duesseldorf-- -
Uncertain significance, no assertion criteria providedliterature onlyInherited Neuropathy Consortium Ii, University Of MiamiJan 06, 2016- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 06, 2013- -
Likely pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 17, 2024This 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 submitterclinical testingGeneDxJan 14, 2025Published 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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 02, 2023PP1, PS3, PS4_moderate -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 08, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
.;D
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Pathogenic
3.4
M;M
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.4
D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.94
MVP
0.91
MPC
1.5
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.60
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.72
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: rs371707778; hg19: chr9-95480229; API