5-31799264-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_178140.4(PDZD2):c.16G>A(p.Asp6Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0139 in 1,604,040 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 32)
  • Exomes 𝑓: 0.014 (197 hom.)
• Consequence: PDZD2 NM_178140.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.83

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PDZD2
• BP4: Computational evidence support a benign effect (MetaRNN=0.007827848).
• BP6: Variant 5-31799264-G-A is Benign according to our data. Variant chr5-31799264-G-A is described in ClinVar as [Benign]. Clinvar id is 776038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0144 (20898/1451722) while in subpopulation NFE AF= 0.017 (18794/1106562). AF 95% confidence interval is 0.0168. There are 197 homozygotes in gnomad4_exome. There are 9891 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDZD2	NM_178140.4	c.16G>A	p.Asp6Asn	missense_variant	2/25	ENST00000438447.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDZD2	ENST00000438447.2	c.16G>A	p.Asp6Asn	missense_variant	2/25	1	NM_178140.4	P1
PDZD2	ENST00000502824.1	n.464G>A		non_coding_transcript_exon_variant	2/3	1
PDZD2	ENST00000513910.1	c.16G>A	p.Asp6Asn	missense_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1433 AN: 152200 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00851 AC: 2083 AN: 244698 Hom.: 13 AF XY: 0.00829 AC XY: 1093 AN XY: 131880

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.000647

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00207

Gnomad FIN exome AF: 0.0202

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00836

GnomAD4 exome AF: 0.0144 AC: 20898 AN: 1451722 Hom.: 197 Cov.: 31 AF XY: 0.0137 AC XY: 9891 AN XY: 721100

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00506

Gnomad4 ASJ exome AF: 0.000749

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00210

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.0170

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00940 AC: 1432 AN: 152318 Hom.: 14 Cov.: 32 AF XY: 0.00916 AC XY: 682 AN XY: 74470

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0132 Hom.: 19

Bravo AF: 0.00846

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.00781 AC: 948

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

PDZD2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 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	0.24
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.073	T;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.010	D;.
Polyphen		1.0	D;.
Vest4		0.32
MVP		0.80
MPC		0.97
ClinPred		0.014	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.53

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: rs116598198; hg19: chr5-31799371; COSMIC: COSV56858071;