9-92719143-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM5 PP2 BP4_Moderate

The NM_001003800.2(BICD2):c.1502G>A(p.Arg501Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R501P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-92719143-C-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, BICD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.15557364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BICD2	NM_001003800.2	c.1502G>A	p.Arg501Gln	missense_variant	5/7	ENST00000356884.11
BICD2	NM_015250.4	c.1502G>A	p.Arg501Gln	missense_variant	5/8
BICD2	XM_017014551.2	c.1583G>A	p.Arg528Gln	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BICD2	ENST00000356884.11	c.1502G>A	p.Arg501Gln	missense_variant	5/7	1	NM_001003800.2	A2
BICD2	ENST00000375512.3	c.1502G>A	p.Arg501Gln	missense_variant	5/8	1		P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459770 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726270

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 07, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 501 of the BICD2 protein (p.Arg501Gln). 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. This variant disrupts the p.Arg501 amino acid residue in BICD2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23664120, 25497877). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is not expected to disrupt BICD2 protein function. ClinVar contains an entry for this variant (Variation ID: 863124). This variant has not been reported in the literature in individuals affected with BICD2-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	19
Dann	Benign	0.80
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.91	N;N
REVEL	Benign	0.028
Sift	Benign	0.75	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.14	B;B
Vest4		0.26
MutPred		0.43		Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);
MVP		0.64
MPC		0.63
ClinPred		0.14	T
GERP RS		2.5
Varity_R		0.018
gMVP		0.30

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

Other links and lift over

dbSNP: rs398123032; hg19: chr9-95481425;