9-92718565-G-C

Position:

• chr9-92718565-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The ENST00000356884.11(BICD2):​c.2080C>G​(p.Arg694Gly) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R694C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BICD2 ENST00000356884.11 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000356884.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• 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, 0.934
• PP5: Variant 9-92718565-G-C is Pathogenic according to our data. Variant chr9-92718565-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 985798.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.2080C>G	p.Arg694Gly	missense_variant	5/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.2080C>G	p.Arg694Gly	missense_variant	5/8		NP_056065.1
BICD2	XM_017014551.2	c.2161C>G	p.Arg721Gly	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>G	p.Arg694Gly	missense_variant	5/7	1	NM_001003800.2	ENSP00000349351	A2
BICD2	ENST00000375512.3	c.2080C>G	p.Arg694Gly	missense_variant	5/8	1		ENSP00000364662	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.041	D
MutationAssessor	Pathogenic	3.5	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.73		Loss of MoRF binding (P = 0.0152);Loss of MoRF binding (P = 0.0152);
MVP		0.90
MPC		1.6
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.92
gMVP		0.81

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;