5-31799415-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_178140.4(PDZD2):c.167C>T(p.Thr56Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,614,124 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (61 hom., cov: 32)
  • Exomes 𝑓: 0.029 (720 hom.)
• Consequence: PDZD2 NM_178140.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.138

Genes affected

PDZD2 (HGNC:18486): (PDZ domain containing 2) The protein encoded by this gene contains six PDZ domains and shares sequence similarity with pro-interleukin-16 (pro-IL-16). Like pro-IL-16, the encoded protein localizes to the endoplasmic reticulum and is thought to be cleaved by a caspase to produce a secreted peptide containing two PDZ domains. In addition, this gene is upregulated in primary prostate tumors and may be involved in the early stages of prostate tumorigenesis. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDZD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.00197196).
• BP6: Variant 5-31799415-C-T is Benign according to our data. Variant chr5-31799415-C-T is described in ClinVar as [Benign]. Clinvar id is 3037252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3252/152280) while in subpopulation NFE AF= 0.0346 (2353/68022). AF 95% confidence interval is 0.0334. There are 61 homozygotes in gnomad4. There are 1551 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD2	NM_178140.4	c.167C>T	p.Thr56Met	missense_variant	2/25	ENST00000438447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD2	ENST00000438447.2	c.167C>T	p.Thr56Met	missense_variant	2/25	1	NM_178140.4	P1
PDZD2	ENST00000502824.1	n.615C>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3252 AN: 152162 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00596

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0270

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0205 AC: 5140 AN: 250458 Hom.: 79 AF XY: 0.0210 AC XY: 2842 AN XY: 135462

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.00836

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0319

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0289 AC: 42285 AN: 1461844 Hom.: 720 Cov.: 32 AF XY: 0.0287 AC XY: 20890 AN XY: 727224

Gnomad4 AFR exome AF: 0.00448

Gnomad4 AMR exome AF: 0.00894

Gnomad4 ASJ exome AF: 0.00375

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.0336

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.0214 AC: 3252 AN: 152280 Hom.: 61 Cov.: 32 AF XY: 0.0208 AC XY: 1551 AN XY: 74456

Gnomad4 AFR AF: 0.00594

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0270

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0298 Hom.: 113

Bravo AF: 0.0191

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0330 AC: 284

ExAC AF: 0.0204 AC: 2479

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PDZD2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	3.4
Dann	Benign	0.95
DEOGEN2	Benign	0.043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.055
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.043	D
Polyphen		0.091	B
Vest4		0.023
MPC		0.52
ClinPred		0.0077	T
GERP RS		0.82
Varity_R		0.032
gMVP		0.31

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: rs145138976; hg19: chr5-31799522; COSMIC: COSV56860890; COSMIC: COSV56860890;