rs1064795760

Variant names:

• chr9-92719006-CATT-C
• rs1064795760
• NM_001003800.2:c.1636_1638delAAT

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_001003800.2(BICD2):​c.1636_1638delAAT​(p.Asn546del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BICD2 NM_001003800.2 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.86
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_001003800.2
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001003800.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-92719006-CATT-C is Pathogenic according to our data. Variant chr9-92719006-CATT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 422408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.1636_1638delAAT	p.Asn546del	conservative_inframe_deletion	Exon 5 of 7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.1636_1638delAAT	p.Asn546del	conservative_inframe_deletion	Exon 5 of 8		NP_056065.1
BICD2	XM_017014551.2	c.1717_1719delAAT	p.Asn573del	conservative_inframe_deletion	Exon 5 of 8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.1636_1638delAAT	p.Asn546del	conservative_inframe_deletion	Exon 5 of 7	1	NM_001003800.2	ENSP00000349351.6
BICD2	ENST00000375512.3	c.1636_1638delAAT	p.Asn546del	conservative_inframe_deletion	Exon 5 of 8	1		ENSP00000364662.3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 19, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 10, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33547725, 30054298) -

Recurrent fractures;C0036572:Seizure;C0151611:EEG abnormality;C0151786:Muscle weakness;C0232466:Feeding difficulties;C0235659:Decreased fetal movement;C0240379:Open mouth;C0426886:Tapered finger;C0541794:Muscular atrophy;C1854882:Absent speech;C1866195:Downturned corners of mouth;C2243051:Macrocephaly;C4551583:Cerebral cortical atrophy;C5779613:Arthrogryposis multiplex congenita Pathogenic:1

Apr 04, 2018

Institute for Genomic Medicine, Nationwide Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.1636_1638delAAT variant results in an in-frame 3 base pair deletion and is predicted to cause loss of an evolutionarily conserved Asparagine residue in a non-repetitive region of the protein (p.Asn546del). It has not been reported in large population cohorts such as gnomAD. In silico modeling suggests that removing the Asn546 disrupts protein secondary structure in a region that has been shown (in mice) to bind KIF5A. This mutation occurred de novo in our patient and was reported by GeneDx in an unrelated patient who shared similar features. We therefore interpret the variant as likely pathogenic. -

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

Jan 30, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064795760; hg19: chr9-95481288;