rs751158467

chr9-92715282-C-Achr9-92715282-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001003800.2(BICD2):c.2440G>T(p.Ala814Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,612,576 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A814T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (1 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.449

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BICD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.027107626).
• BP6: Variant 9-92715282-C-A is Benign according to our data. Variant chr9-92715282-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 579572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000986 (15/152206) while in subpopulation AMR AF= 0.00072 (11/15282). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BICD2	NM_001003800.2	c.2440G>T	p.Ala814Ser	missense_variant	7/7	ENST00000356884.11
BICD2	NM_015250.4	c.2440G>T	p.Ala814Ser	missense_variant	7/8
BICD2	XM_017014551.2	c.2521G>T	p.Ala841Ser	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BICD2	ENST00000356884.11	c.2440G>T	p.Ala814Ser	missense_variant	7/7	1	NM_001003800.2	A2
BICD2	ENST00000375512.3	c.2440G>T	p.Ala814Ser	missense_variant	7/8	1		P4

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000565 AC: 14 AN: 247812 Hom.: 0 AF XY: 0.0000816 AC XY: 11 AN XY: 134806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1460370 Hom.: 1 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 726524

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.0040
Dann	Benign	0.72
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.20	N;N
REVEL	Benign	0.037
Sift	Benign	0.89	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.021	B;B
Vest4		0.10
MutPred		0.21		Loss of loop (P = 9e-04);Loss of loop (P = 9e-04);
MVP		0.30
MPC		0.56
ClinPred		0.021	T
GERP RS		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.024
gMVP		0.096

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: rs751158467; hg19: chr9-95477564; COSMIC: COSV63548167;