22-50277616-G-C

Variant names:

• chr22-50277616-G-C
• rs780142749
• NM_012401.4:c.5171C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012401.4(PLXNB2):​c.5171C>G​(p.Thr1724Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1724M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLXNB2 NM_012401.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

Genes affected

PLXNB2 (HGNC:9104): (plexin B2) Members of the B class of plexins, such as PLXNB2 are transmembrane receptors that participate in axon guidance and cell migration in response to semaphorins (Perrot et al. (2002) [PubMed 12183458]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNB2	NM_012401.4	c.5171C>G	p.Thr1724Arg	missense_variant	Exon 33 of 37	ENST00000359337.9	NP_036533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNB2	ENST00000359337.9	c.5171C>G	p.Thr1724Arg	missense_variant	Exon 33 of 37	5	NM_012401.4	ENSP00000352288.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444626 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 716222

African (AFR) AF: 0.00 AC: 0 AN: 33046

American (AMR) AF: 0.00 AC: 0 AN: 43468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 84590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101420

Other (OTH) AF: 0.00 AC: 0 AN: 59660

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.8	M;M
PhyloP100		7.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.73		Loss of ubiquitination at K1729 (P = 0.0371);Loss of ubiquitination at K1729 (P = 0.0371);
MVP		0.71
MPC		2.0
ClinPred		0.99	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.89
Mutation Taster		=65/35	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: rs780142749; hg19: chr22-50716045;