rs201182504

Variant names:

• chr22-50277610-G-A
• rs201182504
• NM_012401.4:c.5177C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_012401.4(PLXNB2):​c.5177C>T​(p.Thr1726Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000716 in 1,593,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., cov: 34)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: PLXNB2 NM_012401.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000381 (58/152236) while in subpopulation AMR AF = 0.0032 (49/15290). AF 95% confidence interval is 0.00249. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNB2	NM_012401.4	c.5177C>T	p.Thr1726Met	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.5177C>T	p.Thr1726Met	missense_variant	Exon 33 of 37	5	NM_012401.4	ENSP00000352288.4

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152236 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

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: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.0000379 AC: 9 AN: 237764 AF XY: 0.0000155

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000150

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000389 AC: 56 AN: 1440778 Hom.: 0 Cov.: 34 AF XY: 0.0000294 AC XY: 21 AN XY: 713764

African (AFR) AF: 0.00 AC: 0 AN: 33006

American (AMR) AF: 0.000785 AC: 34 AN: 43308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25314

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39326

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 83886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1099120

Other (OTH) AF: 0.000185 AC: 11 AN: 59486

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152236 Hom.: 1 Cov.: 34 AF XY: 0.000296 AC XY: 22 AN XY: 74370

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.00320 AC: 49 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000941

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5177C>T (p.T1726M) alteration is located in exon 33 (coding exon 31) of the PLXNB2 gene. This alteration results from a C to T substitution at nucleotide position 5177, causing the threonine (T) at amino acid position 1726 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;.
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		5.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.50
MutPred		0.69		Gain of methylation at K1729 (P = 0.1014);Gain of methylation at K1729 (P = 0.1014);
MVP		0.46
MPC		1.9
ClinPred		0.72	D
GERP RS		3.9
Varity_R		0.35
gMVP		0.56
Mutation Taster		=82/18	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: rs201182504; hg19: chr22-50716039; COSMIC: COSV63780009; COSMIC: COSV63780009;