22-50278619-C-T

Variant names:

• chr22-50278619-C-T
• rs201459786
• NM_012401.4:c.4624G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS1

The NM_012401.4(PLXNB2):​c.4624G>A​(p.Val1542Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,612,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: PLXNB2 NM_012401.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.382
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09783813).
• BP6: Variant 22-50278619-C-T is Benign according to our data. Variant chr22-50278619-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3934856.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000342 (50/1460662) while in subpopulation NFE AF = 0.0000369 (41/1111790). AF 95% confidence interval is 0.0000274. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNB2	NM_012401.4	c.4624G>A	p.Val1542Ile	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.4624G>A	p.Val1542Ile	missense_variant	Exon 29 of 37	5	NM_012401.4	ENSP00000352288.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246896 AF XY: 0.0000446

Gnomad AFR exome AF: 0.0000657

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1460662 Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19 AN XY: 726656

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86218

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: 0.0000369 AC: 41 AN: 1111790

Other (OTH) AF: 0.0000828 AC: 5 AN: 60354

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 06, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.2
DANN	Benign	0.89
DEOGEN2	Benign	0.012	.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Benign	-0.94	T
PhyloP100		0.38
Sift4G	Benign	0.28	T;T
MVP		0.49
ClinPred		0.012	T
GERP RS		-0.43
Varity_R		0.093
Mutation Taster		=96/4	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: rs201459786; hg19: chr22-50717048; COSMIC: COSV104421033; COSMIC: COSV104421033;