10-20217531-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032812.9(PLXDC2):c.1228A>G(p.Arg410Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PLXDC2 NM_032812.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.342

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13705468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXDC2	NM_032812.9	c.1228A>G	p.Arg410Gly	missense_variant	11/14	ENST00000377252.5
PLXDC2	NM_001282736.2	c.1081A>G	p.Arg361Gly	missense_variant	10/13
PLXDC2	XM_011519750.3	c.1228A>G	p.Arg410Gly	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXDC2	ENST00000377252.5	c.1228A>G	p.Arg410Gly	missense_variant	11/14	1	NM_032812.9	P1
PLXDC2	ENST00000377242.7	c.1081A>G	p.Arg361Gly	missense_variant	10/13	1
PLXDC2	ENST00000377238.2	n.1003A>G		non_coding_transcript_exon_variant	10/13	5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452978 Hom.: 0 Cov.: 56 AF XY: 0.00000277 AC XY: 2 AN XY: 722846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.1228A>G (p.R410G) alteration is located in exon 11 (coding exon 11) of the PLXDC2 gene. This alteration results from a A to G substitution at nucleotide position 1228, causing the arginine (R) at amino acid position 410 to be replaced by a glycine (G). 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	0.083
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	14
Dann	Benign	0.96
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.60	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;T
Sift4G	Benign	0.36	T;T
Polyphen		0.010	B;B
Vest4		0.60
MutPred		0.27		.;Gain of methylation at R411 (P = 0.0304);
MVP		0.28
MPC		0.016
ClinPred		0.080	T
GERP RS		-0.20
Varity_R		0.088
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs752472328; hg19: chr10-20506460;