rs756538071

Variant names:

• chr9-92717863-T-C
• rs756538071
• NM_001003800.2:c.2192A>G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PP3 BP6_Very_Strong BS2

The NM_001003800.2(BICD2):​c.2192A>G​(p.Asn731Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: BICD2 NM_001003800.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.93

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 -9 ACMG points.

• PM1: In a coiled_coil_region (size 142) in uniprot entity BICD2_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001003800.2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• BP6: Variant 9-92717863-T-C is Benign according to our data. Variant chr9-92717863-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BICD2	NM_001003800.2	c.2192A>G	p.Asn731Ser	missense_variant	Exon 6 of 7	ENST00000356884.11	NP_001003800.1
BICD2	NM_015250.4	c.2192A>G	p.Asn731Ser	missense_variant	Exon 6 of 8		NP_056065.1
BICD2	XM_017014551.2	c.2273A>G	p.Asn758Ser	missense_variant	Exon 6 of 8		XP_016870040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BICD2	ENST00000356884.11	c.2192A>G	p.Asn731Ser	missense_variant	Exon 6 of 7	1	NM_001003800.2	ENSP00000349351.6
BICD2	ENST00000375512.3	c.2192A>G	p.Asn731Ser	missense_variant	Exon 6 of 8	1		ENSP00000364662.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251322 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135858

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460804 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 726730

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74320

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 22, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.96	D;D
Vest4		0.74
MutPred		0.61		Gain of phosphorylation at N731 (P = 0.0323);Gain of phosphorylation at N731 (P = 0.0323);
MVP		0.71
MPC		1.2
ClinPred		0.81	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.46

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: rs756538071; hg19: chr9-95480145;