chr10-19817093-C-G

Variant names:

• chr10-19817093-C-G
• rs760347802
• NM_032812.9:c.14C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032812.9(PLXDC2):​c.14C>G​(p.Pro5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000791 in 1,555,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P5T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: PLXDC2 NM_032812.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.444
• Publications: 0 publications found

Genes affected

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

ENSG00000285852 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0223912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXDC2	NM_032812.9	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 14	ENST00000377252.5	NP_116201.7
PLXDC2	NM_001282736.2	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 13		NP_001269665.1
PLXDC2	XM_011519750.3	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 14		XP_011518052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXDC2	ENST00000377252.5	c.14C>G	p.Pro5Arg	missense_variant	Exon 1 of 14	1	NM_032812.9	ENSP00000366460.3

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000245 AC: 4 AN: 163406 AF XY: 0.0000230

Gnomad AFR exome AF: 0.00

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: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000827 AC: 116 AN: 1403116 Hom.: 0 Cov.: 32 AF XY: 0.0000779 AC XY: 54 AN XY: 692800

African (AFR) AF: 0.00 AC: 0 AN: 31694

American (AMR) AF: 0.00 AC: 0 AN: 36962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25386

East Asian (EAS) AF: 0.00 AC: 0 AN: 35972

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.0000888 AC: 96 AN: 1080828

Other (OTH) AF: 0.000327 AC: 19 AN: 58114

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74256

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000180 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>G (p.P5R) alteration is located in exon 1 (coding exon 1) of the PLXDC2 gene. This alteration results from a C to G substitution at nucleotide position 14, causing the proline (P) at amino acid position 5 to be replaced by an arginine (R). 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	0.042
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.021	.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N
PhyloP100		-0.44
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.047
Sift	Benign	1.0	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0	B;B
Vest4		0.12
MVP		0.043
MPC		0.12
ClinPred		0.032	T
GERP RS		-3.0
Varity_R		0.085
gMVP		0.11
Mutation Taster		=88/12	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: rs760347802; hg19: chr10-20106022;