9-92715207-C-T

Position:

chr9-92715207-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_001003800.2(BICD2):c.2515G>A(p.Gly839Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

BICD2
NM_001003800.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.69

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]

BICD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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=0.20119366).

BP6

Variant 9-92715207-C-T is Benign according to our data. Variant chr9-92715207-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 565422.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BICD2	NM_001003800.2 linkuse as main transcript	c.2515G>A	p.Gly839Arg	missense_variant	7/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4 linkuse as main transcript	c.2469+46G>A		intron_variant			NP_056065.1
BICD2	XM_017014551.2 linkuse as main transcript	c.2550+46G>A		intron_variant			XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11 linkuse as main transcript	c.2515G>A	p.Gly839Arg	missense_variant	7/7	1	NM_001003800.2	ENSP00000349351	A2	Q8TD16-2
BICD2	ENST00000375512.3 linkuse as main transcript	c.2469+46G>A		intron_variant		1		ENSP00000364662	P4	Q8TD16-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249100

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134956

show subpopulations

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:

0.0000535

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1459614

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

725858

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:

0.0000495

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spastic paraplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2022

The p.G839R variant (also known as c.2515G>A), located in coding exon 7 of the BICD2 gene, results from a G to A substitution at nucleotide position 2515. The glycine at codon 839 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in two siblings with lower extremity-predominant spinal muscular atrophy 2 (SMALED2) and a family history of relatives with similar clinical features (Rudnik-Schöneborn S et al. Muscle Nerve, 2016 09;54:496-500). This amino acid position is not well conserved in available vertebrate species. 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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.82

M_CAP

Benign

0.047

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.31

REVEL

Benign

0.033

Sift

Benign

0.14

Sift4G

Benign

0.37

Polyphen

0.92

Vest4

0.27

MutPred

0.26

Loss of helix (P = 0.0138);

MVP

0.50

MPC

0.99

ClinPred

0.58

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.22

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over