rs908773556

Positions:

• chr9-92719063-C-A
• chr9-92719063-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001003800.2(BICD2):​c.1582G>T​(p.Val528Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. V528M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001003800.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BICD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.37244582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BICD2	NM_001003800.2	c.1582G>T	p.Val528Leu	missense_variant	5/7	ENST00000356884.11
BICD2	NM_015250.4	c.1582G>T	p.Val528Leu	missense_variant	5/8
BICD2	XM_017014551.2	c.1663G>T	p.Val555Leu	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BICD2	ENST00000356884.11	c.1582G>T	p.Val528Leu	missense_variant	5/7	1	NM_001003800.2	A2
BICD2	ENST00000375512.3	c.1582G>T	p.Val528Leu	missense_variant	5/8	1		P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249734 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135322

Gnomad AFR exome AF: 0.00

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: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460754 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726730

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

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

Nov 12, 2021

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. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 528 of the BICD2 protein (p.Val528Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BICD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 949380). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.27	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.84	P;P
Vest4		0.31
MutPred		0.62		Gain of disorder (P = 0.1803);Gain of disorder (P = 0.1803);
MVP		0.77
MPC		0.56
ClinPred		0.50	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.75

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: rs908773556; hg19: chr9-95481345;