Genetic Variant PLXDC2:p.Glu108Lys (chr10-20001984-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032812.9(PLXDC2):c.322G>A(p.Glu108Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000137 in 1,458,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PLXDC2
NM_032812.9 missense, splice_region

Scores

Splicing: ADA: 0.5985

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.50

Variant links:

Genes affected

PLXDC2 (HGNC:21013): (plexin domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLXDC2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXDC2	NM_032812.9 link	c.322G>A	p.Glu108Lys	missense_variant, splice_region_variant	Exon 2 of 14	ENST00000377252.5	NP_116201.7	Q6UX71-1
PLXDC2	NM_001282736.2 link	c.322G>A	p.Glu108Lys	missense_variant, splice_region_variant	Exon 2 of 13		NP_001269665.1	Q6UX71-2
PLXDC2	XM_011519750.3 link	c.322G>A	p.Glu108Lys	missense_variant, splice_region_variant	Exon 2 of 14		XP_011518052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXDC2	ENST00000377252.5 link	c.322G>A	p.Glu108Lys	missense_variant, splice_region_variant	Exon 2 of 14	1	NM_032812.9	ENSP00000366460.3		Q6UX71-1
PLXDC2	ENST00000377242.7 link	c.322G>A	p.Glu108Lys	missense_variant, splice_region_variant	Exon 2 of 13	1		ENSP00000366450.3		Q6UX71-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1458758

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725506

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322G>A (p.E108K) alteration is located in exon 2 (coding exon 2) of the PLXDC2 gene. This alteration results from a G to A substitution at nucleotide position 322, causing the glutamic acid (E) at amino acid position 108 to be replaced by a lysine (K). 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

0.28

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.46

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.36

T;T

Sift4G

Benign

0.83

T;T

Polyphen

1.0

D;P

Vest4

0.88

MutPred

0.37

Gain of ubiquitination at E108 (P = 0.0069);Gain of ubiquitination at E108 (P = 0.0069);

MVP

0.26

MPC

0.16

ClinPred

0.86

GERP RS

5.8

Varity_R

0.13

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.60

dbscSNV1_RF

Benign

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over