rs398123028

Variant names:

• chr9-92729157-G-A
• rs398123028
• NM_001003800.2:c.320C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001003800.2(BICD2):​c.320C>T​(p.Ser107Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.77

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 9-92729157-G-A is Pathogenic according to our data. Variant chr9-92729157-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92729157-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.320C>T	p.Ser107Leu	missense_variant	Exon 2 of 7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.320C>T	p.Ser107Leu	missense_variant	Exon 2 of 8		NP_056065.1
BICD2	XM_017014551.2	c.401C>T	p.Ser134Leu	missense_variant	Exon 2 of 8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.320C>T	p.Ser107Leu	missense_variant	Exon 2 of 7	1	NM_001003800.2	ENSP00000349351.6
BICD2	ENST00000375512.3	c.320C>T	p.Ser107Leu	missense_variant	Exon 2 of 8	1		ENSP00000364662.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Pathogenic:4

Jun 06, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 25, 2018

Institute of Human Genetics, Cologne University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 07, 2022

Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.320C>T (p.Ser107Leu) BICD2 variant has been reported in our laboratory in a 29-year-old patient from Uruguay with diagnosis of distal muscular attrophy. This variant is a de novo change (parents and two asymptomatic siblings) and it has been previously reported in a patients with spinal muscular atrophy [PMID 8114789, 22628388, 23664116, 23664119, 23664120, 25497877, 27784775, 28251916]. This variant is not present in population databases ( gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 55857). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116). In summary, c.523C>T TRPC6 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity and experimental studies, de novo occurrence in this family and having been widely described in relation to the patient´s phenotype. -

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 107 of the BICD2 protein (p.Ser107Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spinal muscular atrophy (SMA) (PMID: 23664116, 23664119, 23664120, 25497877, 27784775, 28251916). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55857). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) did not meet the statistical confidence thresholds required to predict the impact of this variant on BICD2 function. Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Jan 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant alters protein function by increasing protein binding affinity and causing the abnormal accumulation of BICD2 protein (Peeters et al., 2013; Oates et al., 2013; Unger et al., 2016); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26063656, 23664119, 25497877, 23664116, 27784775, 26594138, 28251916, 28883039, 23664120, 29528393, 22628388, 8114789, 31127727, 32056343) -

Jul 23, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM1, PM2, PM6, PS3, PS4_moderate -

Distal myopathy Pathogenic:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Zygosity: heterozygous -

Neuronopathy, distal hereditary motor, autosomal dominant Pathogenic:1

-

Inherited Neuropathy Consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Spinal muscular atrophy Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.66		Loss of phosphorylation at S107 (P = 0.043);Loss of phosphorylation at S107 (P = 0.043);
MVP		0.87
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.67

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: rs398123028; hg19: chr9-95491439;