rs61754130

Positions:

• chr9-92729208-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001003800.2(BICD2):​c.269A>G​(p.Lys90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00553 in 1,614,180 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (32 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.66

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 Benign. Variant got -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009992003).
• BP6: Variant 9-92729208-T-C is Benign according to our data. Variant chr9-92729208-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235235.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=4}. Variant chr9-92729208-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00434 (661/152340) while in subpopulation NFE AF= 0.0072 (490/68034). AF 95% confidence interval is 0.00668. There are 3 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.269A>G	p.Lys90Arg	missense_variant	2/7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.269A>G	p.Lys90Arg	missense_variant	2/8		NP_056065.1
BICD2	XM_017014551.2	c.350A>G	p.Lys117Arg	missense_variant	2/8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.269A>G	p.Lys90Arg	missense_variant	2/7	1	NM_001003800.2	ENSP00000349351.6
BICD2	ENST00000375512.3	c.269A>G	p.Lys90Arg	missense_variant	2/8	1		ENSP00000364662.3

Frequencies

GnomAD3 genomes AF: 0.00435 AC: 662 AN: 152222 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00744

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00459 AC: 1151 AN: 251024 Hom.: 6 AF XY: 0.00480 AC XY: 651 AN XY: 135674

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00711

Gnomad NFE exome AF: 0.00703

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00566 AC: 8269 AN: 1461840 Hom.: 32 Cov.: 32 AF XY: 0.00565 AC XY: 4106 AN XY: 727220

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00387

Gnomad4 FIN exome AF: 0.00860

Gnomad4 NFE exome AF: 0.00641

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152340 Hom.: 3 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74504

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00744

Gnomad4 NFE AF: 0.00720

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00621 Hom.: 6

Bravo AF: 0.00369

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00470 AC: 571

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00581

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BICD2: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2019	This variant is associated with the following publications: (PMID: 23664116, 27549087) -

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde

Mar 07, 2017

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 21, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Neuronopathy, distal hereditary motor, autosomal dominant Benign:1

Benign, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

BICD2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.36	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.051
Sift	Benign	0.71	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0010	B;B
Vest4		0.21
MVP		0.74
MPC		0.44
ClinPred		0.0066	T
GERP RS		4.1
Varity_R		0.072
gMVP		0.093

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: rs61754130; hg19: chr9-95491490;