rs2778979

Positions:

• chr10-20245404-A-G
• chr10-20245404-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032812.9(PLXDC2):​c.1372A>G​(p.Ile458Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.879 in 1,613,752 control chromosomes in the GnomAD database, including 627,645 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.88 (58958 hom., cov: 32)
  • Exomes 𝑓: 0.88 (568687 hom.)
• Consequence: PLXDC2 NM_032812.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.755998E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXDC2	NM_032812.9	c.1372A>G	p.Ile458Val	missense_variant	13/14	ENST00000377252.5
PLXDC2	NM_001282736.2	c.1225A>G	p.Ile409Val	missense_variant	12/13
PLXDC2	XM_011519750.3	c.1372A>G	p.Ile458Val	missense_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXDC2	ENST00000377252.5	c.1372A>G	p.Ile458Val	missense_variant	13/14	1	NM_032812.9	P1
PLXDC2	ENST00000377242.7	c.1225A>G	p.Ile409Val	missense_variant	12/13	1
PLXDC2	ENST00000377238.2	n.1147A>G		non_coding_transcript_exon_variant	12/13	5

Frequencies

GnomAD3 genomes AF: 0.876 AC: 133289 AN: 152074 Hom.: 58919 Cov.: 32

Gnomad AFR AF: 0.919

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.927

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.813

Gnomad FIN AF: 0.838

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.877

GnomAD3 exomes AF: 0.827 AC: 207604 AN: 251110 Hom.: 87826 AF XY: 0.836 AC XY: 113413 AN XY: 135722

Gnomad AFR exome AF: 0.918

Gnomad AMR exome AF: 0.641

Gnomad ASJ exome AF: 0.929

Gnomad EAS exome AF: 0.556

Gnomad SAS exome AF: 0.829

Gnomad FIN exome AF: 0.829

Gnomad NFE exome AF: 0.902

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.879 AC: 1284569 AN: 1461560 Hom.: 568687 Cov.: 56 AF XY: 0.879 AC XY: 639175 AN XY: 727096

Gnomad4 AFR exome AF: 0.927

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.582

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.825

Gnomad4 NFE exome AF: 0.902

Gnomad4 OTH exome AF: 0.870

GnomAD4 genome AF: 0.876 AC: 133384 AN: 152192 Hom.: 58958 Cov.: 32 AF XY: 0.871 AC XY: 64846 AN XY: 74428

Gnomad4 AFR AF: 0.919

Gnomad4 AMR AF: 0.777

Gnomad4 ASJ AF: 0.927

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.813

Gnomad4 FIN AF: 0.838

Gnomad4 NFE AF: 0.903

Gnomad4 OTH AF: 0.878

Alfa AF: 0.894 Hom.: 149480

Bravo AF: 0.871

TwinsUK AF: 0.911 AC: 3377

ALSPAC AF: 0.895 AC: 3451

ESP6500AA AF: 0.920 AC: 4053

ESP6500EA AF: 0.904 AC: 7775

ExAC AF: 0.837 AC: 101578

Asia WGS AF: 0.714 AC: 2485 AN: 3478

EpiCase AF: 0.912

EpiControl AF: 0.908

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.46
DEOGEN2	Benign	0.0047	.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.11	T;T
MetaRNN	Benign	5.8e-7	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	.;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.080	N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.053
MPC		0.015
ClinPred		0.00076	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2778979; hg19: chr10-20534333; COSMIC: COSV65901940;