rs754018322

Variant names:

• chr9-92718996-T-C
• rs754018322
• NM_001003800.2:c.1649A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_001003800.2(BICD2):​c.1649A>G​(p.Asn550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,459,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.34
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001003800.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.34750676).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BICD2	NM_001003800.2	MANE Select	c.1649A>G	p.Asn550Ser	missense	Exon 5 of 7	NP_001003800.1
	BICD2	NM_015250.4		c.1649A>G	p.Asn550Ser	missense	Exon 5 of 8	NP_056065.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BICD2	ENST00000356884.11	TSL:1 MANE Select	c.1649A>G	p.Asn550Ser	missense	Exon 5 of 7	ENSP00000349351.6
	BICD2	ENST00000375512.3	TSL:1	c.1649A>G	p.Asn550Ser	missense	Exon 5 of 8	ENSP00000364662.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000365 AC: 9 AN: 246890 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000816

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459420 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 726108

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5410

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111922

Other (OTH) AF: 0.0000166 AC: 1 AN: 60324

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.080
Sift	Benign	0.22	T
Sift4G	Benign	0.34	T
Polyphen		0.18	B
Vest4		0.39
MVP		0.57
MPC		0.44
ClinPred		0.12	T
GERP RS		1.9
Varity_R		0.058
gMVP		0.71
Mutation Taster		=79/21	polymorphism

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: rs754018322; hg19: chr9-95481278; COSMIC: COSV100794120;