5-31983354-C-A

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.676C>A(p.Pro226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000936 in 1,614,178 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: PDZD2 NM_178140.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.291

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=0.0019925833).
• BP6: Variant 5-31983354-C-A is Benign according to our data. Variant chr5-31983354-C-A is described in ClinVar as [Benign]. Clinvar id is 3043864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00527 (803/152294) while in subpopulation AFR AF= 0.0184 (766/41552). AF 95% confidence interval is 0.0174. There are 9 homozygotes in gnomad4. There are 387 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD2	NM_178140.4	c.676C>A	p.Pro226Thr	missense_variant	3/25	ENST00000438447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD2	ENST00000438447.2	c.676C>A	p.Pro226Thr	missense_variant	3/25	1	NM_178140.4	P1
PDZD2	ENST00000502489.5	n.432C>A		non_coding_transcript_exon_variant	2/18	2
PDZD2	ENST00000513852.1	n.395C>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 152176 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

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: 0.00

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00127 AC: 318 AN: 251332 Hom.: 3 AF XY: 0.000839 AC XY: 114 AN XY: 135832

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000484 AC: 708 AN: 1461884 Hom.: 6 Cov.: 32 AF XY: 0.000415 AC XY: 302 AN XY: 727244

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00527 AC: 803 AN: 152294 Hom.: 9 Cov.: 33 AF XY: 0.00520 AC XY: 387 AN XY: 74472

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.000987 Hom.: 4

Bravo AF: 0.00559

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00149 AC: 181

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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 18, 2019

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	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	7.6
Dann	Benign	0.79
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.019
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.38	T
Polyphen		0.48	P
Vest4		0.12
MVP		0.13
MPC		0.44
ClinPred		0.0065	T
GERP RS		-2.7
Varity_R		0.064
gMVP		0.68

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: rs34239074; hg19: chr5-31983460; COSMIC: COSV99031175;