9-92764542-T-C

Position:

• chr9-92764542-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001003800.2(BICD2):​c.203A>G​(p.Tyr68Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,392,224 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.80

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BICD2. . Gene score misZ 2.205 (greater than the threshold 3.09). Trascript score misZ 3.1082 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20268142).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.203A>G	p.Tyr68Cys	missense_variant	1/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.203A>G	p.Tyr68Cys	missense_variant	1/8		NP_056065.1
BICD2	XM_017014551.2	c.203A>G	p.Tyr68Cys	missense_variant	1/8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.203A>G	p.Tyr68Cys	missense_variant	1/7	1	NM_001003800.2	ENSP00000349351.6
BICD2	ENST00000375512.3	c.203A>G	p.Tyr68Cys	missense_variant	1/8	1		ENSP00000364662.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000686 AC: 1 AN: 145850 Hom.: 0 AF XY: 0.0000128 AC XY: 1 AN XY: 78028

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: 0.0000464

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1392224 Hom.: 0 Cov.: 31 AF XY: 0.0000160 AC XY: 11 AN XY: 686822

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: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00000908 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The p.Y68C variant (also known as c.203A>G), located in coding exon 1 of the BICD2 gene, results from an A to G substitution at nucleotide position 203. The tyrosine at codon 68 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. 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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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: 541285). This variant has not been reported in the literature in individuals affected with BICD2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 68 of the BICD2 protein (p.Tyr68Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.32	.;T
Eigen	Benign	-0.097
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.14
Sift	Benign	0.23	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.0030	B;B
Vest4		0.48
MVP		0.70
MPC		0.70
ClinPred		0.57	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.53

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: rs141519259; hg19: chr9-95526824;