chr22-50278634-C-T

Variant names:

• chr22-50278634-C-T
• NM_012401.4:c.4609G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_012401.4(PLXNB2):​c.4609G>A​(p.Gly1537Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,786 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLXNB2 NM_012401.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.99
• 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, 0.777
• PP5: Variant 22-50278634-C-T is Pathogenic according to our data. Variant chr22-50278634-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1895428.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNB2	NM_012401.4	c.4609G>A	p.Gly1537Ser	missense_variant	Exon 29 of 37	ENST00000359337.9	NP_036533.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNB2	ENST00000359337.9	c.4609G>A	p.Gly1537Ser	missense_variant	Exon 29 of 37	5	NM_012401.4	ENSP00000352288.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460786 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

See cases Pathogenic:1

Jan 04, 2023

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Variant not identified in gnomAD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0078	.;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-1.1	T
PhyloP100		6.0
Sift4G	Benign	0.28	T;T
MVP		0.74
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.51
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr22-50717063;