rs797045412

Positions:

• chr9-92718565-G-A
• chr9-92718565-G-C
• chr9-92718565-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001003800.2(BICD2):​c.2080C>T​(p.Arg694Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 3.16

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 17 ACMG points.

• PM1: In a coiled_coil_region (size 142) in uniprot entity BICD2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001003800.2
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 9-92718565-G-A is Pathogenic according to our data. Variant chr9-92718565-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-92718565-G-A is described in Lovd as [Likely_pathogenic]. Variant chr9-92718565-G-A is described in Lovd as [Pathogenic]. Variant chr9-92718565-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.2080C>T	p.Arg694Cys	missense_variant	5/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.2080C>T	p.Arg694Cys	missense_variant	5/8		NP_056065.1
BICD2	XM_017014551.2	c.2161C>T	p.Arg721Cys	missense_variant	5/8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.2080C>T	p.Arg694Cys	missense_variant	5/7	1	NM_001003800.2	ENSP00000349351	A2
BICD2	ENST00000375512.3	c.2080C>T	p.Arg694Cys	missense_variant	5/8	1		ENSP00000364662	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 27, 2022	ACMG classification criteria: PS4 moderated, PM2 moderated, PM6 moderated, PP3 supporting -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 10, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2022

Identified in a patient with arthrogryposis multiplex congenita, micrognathia, and respiratory insufficiency requiring assisted ventilation in published literature (Storbeck et al., 2017) but familial segregation information was not included; 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: 33060286, 32709491, 32665036, 27751653, 25998610, 28688748, 29274205, 32888736, 33547725, 32057122, 32056343, 33726816, 35896821, Ribeiro-Mourao2022[Article], 34736627, 35616356, 31655624, 28635954) -

Spinal muscular atrophy, lower extremity-predominant, 2b, prenatal onset, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 30, 2019

- -

Spinal muscular atrophy, lower extremity-predominant, 2, AD Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 17, 2014

- -

Autosomal dominant hereditary axonal motor and sensory neuropathy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jun 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.091	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.72		Loss of MoRF binding (P = 0.0028);Loss of MoRF binding (P = 0.0028);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.79

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: rs797045412; hg19: chr9-95480847;