rs202119238

Positions:

chr9-92719576-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2

The NM_001003800.2(BICD2):c.1069C>T(p.Arg357Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,600,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

BICD2
NM_001003800.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.36

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 -8 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.

BP6

Variant 9-92719576-G-A is Benign according to our data. Variant chr9-92719576-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 423187.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152268) while in subpopulation AMR AF= 0.000588 (9/15306). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BICD2	NM_001003800.2 linkuse as main transcript	c.1069C>T	p.Arg357Trp	missense_variant	5/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4 linkuse as main transcript	c.1069C>T	p.Arg357Trp	missense_variant	5/8		NP_056065.1
BICD2	XM_017014551.2 linkuse as main transcript	c.1150C>T	p.Arg384Trp	missense_variant	5/8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11 linkuse as main transcript	c.1069C>T	p.Arg357Trp	missense_variant	5/7	1	NM_001003800.2	ENSP00000349351	A2	Q8TD16-2
BICD2	ENST00000375512.3 linkuse as main transcript	c.1069C>T	p.Arg357Trp	missense_variant	5/8	1		ENSP00000364662	P4	Q8TD16-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000289

AC:

AN:

235274

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

128196

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000356

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000263

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.000205

AC:

297

AN:

1447964

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

130

AN XY:

719472

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.000499

Gnomad4 ASJ exome

AF:

0.00136

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000703

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000185

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.000217

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 27, 2017

The R357W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R357W variant is observed in 31/47044 (0.07%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R357W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.56

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

1.0

D;D

Vest4

0.84

MVP

0.88

MPC

1.5

ClinPred

0.48

GERP RS

1.7

Varity_R

0.49

gMVP

0.37

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