10-101010536-TGCTGCGGCTGCG-TGCTGCGGCTGCGGCTGCGGCTGCGGCTACGGCTGCGGCTGCGGCTGCG

Variant names:

• chr10-101010536-T-TGCTGCGGCTGCGGCTGCGGCTGCGGCTACGGCTGCG
• rs200896335
• NM_001195263.2:c.2352_2353insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001195263.2(PDZD7):​c.2352_2353insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC​(p.Ser784_Ser785insArgSerArgSerArgSerArgSerArgSerArgSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDZD7 NM_001195263.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.894
• Publications: 10 publications found

Genes affected

PDZD7 (HGNC:26257): (PDZ domain containing 7) This gene encodes a ciliary protein homologous to proteins which are mutated in Usher syndrome patients, and mutations and translocations involving this gene have been associated with two types of Usher syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

PDZD7 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 2C

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001195263.2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2	c.2352_2353insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSerArgSerArgSerArgSerArgSer	conservative_inframe_insertion	Exon 15 of 17	ENST00000619208.6	NP_001182192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDZD7	ENST00000619208.6	c.2352_2353insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC	p.Ser784_Ser785insArgSerArgSerArgSerArgSerArgSerArgSer	conservative_inframe_insertion	Exon 15 of 17	5	NM_001195263.2	ENSP00000480489.1
PDZD7	ENST00000474125.7	n.*2299_*2300insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC		non_coding_transcript_exon_variant	Exon 11 of 13	2		ENSP00000474447.1
PDZD7	ENST00000474125.7	n.*2299_*2300insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC		3_prime_UTR_variant	Exon 11 of 13	2		ENSP00000474447.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151384 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000437 AC: 6 AN: 1372456 Hom.: 0 Cov.: 98 AF XY: 0.00000740 AC XY: 5 AN XY: 675330

African (AFR) AF: 0.00 AC: 0 AN: 31396

American (AMR) AF: 0.0000849 AC: 3 AN: 35320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24594

East Asian (EAS) AF: 0.00 AC: 0 AN: 35512

South Asian (SAS) AF: 0.00 AC: 0 AN: 78340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.34e-7 AC: 1 AN: 1070816

Other (OTH) AF: 0.0000349 AC: 2 AN: 57346

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151384 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73840

African (AFR) AF: 0.00 AC: 0 AN: 41280

American (AMR) AF: 0.0000657 AC: 1 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10446

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67706

Other (OTH) AF: 0.00 AC: 0 AN: 2076

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2352_2353insCGCAGCCGTAGCCGCAGCCGCAGCCGCAGCCGCAGC, results in the insertion of 12 amino acid(s) of the PDZD7 protein (p.Arg773_Ser784dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PDZD7-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200896335; hg19: chr10-102770293;