rs748022488

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

The NM_001003800.2(BICD2):c.1696C>T(p.Arg566Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000578 in 1,609,296 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.000053 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

BICD2
NM_001003800.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.31

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 Benign. Variant got -9 ACMG points.

PM1

In a region_of_interest Interaction with KIF5A (size 265) in uniprot entity BICD2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001003800.2

BP4

Computational evidence support a benign effect (MetaRNN=0.25104356).

BP6

Variant 9-92718949-G-A is Benign according to our data. Variant chr9-92718949-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570965.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000526 (8/152162) while in subpopulation SAS AF= 0.00062 (3/4836). AF 95% confidence interval is 0.000169. There are 1 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BICD2	NM_001003800.2 link	c.1696C>T	p.Arg566Cys	missense_variant	Exon 5 of 7	ENST00000356884.11	NP_001003800.1	Q8TD16-2Q96FU2
BICD2	NM_015250.4 link	c.1696C>T	p.Arg566Cys	missense_variant	Exon 5 of 8		NP_056065.1	Q8TD16-1Q96FU2
BICD2	XM_017014551.2 link	c.1777C>T	p.Arg593Cys	missense_variant	Exon 5 of 8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11 link	c.1696C>T	p.Arg566Cys	missense_variant	Exon 5 of 7	1	NM_001003800.2	ENSP00000349351.6		Q8TD16-2
BICD2	ENST00000375512.3 link	c.1696C>T	p.Arg566Cys	missense_variant	Exon 5 of 8	1		ENSP00000364662.3		Q8TD16-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000583

AC:

AN:

240276

Hom.:

AF XY:

0.0000609

AC XY:

AN XY:

131424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000376

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000583

AC:

AN:

1457134

Hom.:

Cov.:

AF XY:

0.0000648

AC XY:

AN XY:

725018

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000325

Gnomad4 FIN exome

AF:

0.0000398

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000620

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000465

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000745

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

BICD2-related disorder

Uncertain:1

Nov 18, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BICD2 c.1696C>T variant is predicted to result in the amino acid substitution p.Arg566Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-95481231-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Nov 04, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

.;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.17

Sift

Benign

0.069

T;T

Sift4G

Benign

0.061

T;T

Polyphen

0.97

D;D

Vest4

0.31

MutPred

0.55

Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);

MVP

0.74

MPC

1.2

ClinPred

0.090

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.55

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