rs397516634

Variant names:

• chr10-101010552-GCGGCTACGGCTGCGGCTA-G
• rs397516634
• NM_001195263.2:c.2319_2336delTAGCCGCAGCCGTAGCCG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001195263.2(PDZD7):​c.2319_2336delTAGCCGCAGCCGTAGCCG​(p.Ser774_Arg779del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 1,524,830 control chromosomes in the GnomAD database, including 120 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R773R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0067 (5 hom., cov: 28)
  • Exomes 𝑓: 0.010 (115 hom.)
• Consequence: PDZD7 NM_001195263.2 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.36
• Publications: 1 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: Unknown Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive 57

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

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001195263.2
• BP6: Variant 10-101010552-GCGGCTACGGCTGCGGCTA-G is Benign according to our data. Variant chr10-101010552-GCGGCTACGGCTGCGGCTA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00673 (1021/151680) while in subpopulation NFE AF = 0.011 (746/67720). AF 95% confidence interval is 0.0104. There are 5 homozygotes in GnomAd4. There are 477 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195263.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	NM_001195263.2	MANE Select	c.2319_2336delTAGCCGCAGCCGTAGCCG	p.Ser774_Arg779del	disruptive_inframe_deletion	Exon 15 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.2316_2333delTAGCCGCAGCCGTAGCCG	p.Ser773_Arg778del	disruptive_inframe_deletion	Exon 15 of 17	NP_001424358.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.2319_2336delTAGCCGCAGCCGTAGCCG	p.Ser774_Arg779del	disruptive_inframe_deletion	Exon 15 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.2316_2333delTAGCCGCAGCCGTAGCCG	p.Ser773_Arg778del	disruptive_inframe_deletion	Exon 15 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2266_*2283delTAGCCGCAGCCGTAGCCG		non_coding_transcript_exon	Exon 11 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.00674 AC: 1021 AN: 151560 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.00201

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00807

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00418

Gnomad FIN AF: 0.000757

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00866

GnomAD2 exomes AF: 0.00624 AC: 818 AN: 130986 AF XY: 0.00621

Gnomad AFR exome AF: 0.000779

Gnomad AMR exome AF: 0.00404

Gnomad ASJ exome AF: 0.00521

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00118

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.0103 AC: 14150 AN: 1373150 Hom.: 115 AF XY: 0.0101 AC XY: 6813 AN XY: 676036

African (AFR) AF: 0.00166 AC: 52 AN: 31356

American (AMR) AF: 0.00446 AC: 158 AN: 35426

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 141 AN: 24846

East Asian (EAS) AF: 0.000169 AC: 6 AN: 35474

South Asian (SAS) AF: 0.00393 AC: 309 AN: 78622

European-Finnish (FIN) AF: 0.00154 AC: 52 AN: 33676

Middle Eastern (MID) AF: 0.0229 AC: 129 AN: 5642

European-Non Finnish (NFE) AF: 0.0119 AC: 12762 AN: 1070732

Other (OTH) AF: 0.00943 AC: 541 AN: 57376

GnomAD4 genome AF: 0.00673 AC: 1021 AN: 151680 Hom.: 5 Cov.: 28 AF XY: 0.00643 AC XY: 477 AN XY: 74142

African (AFR) AF: 0.00200 AC: 83 AN: 41412

American (AMR) AF: 0.00806 AC: 123 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5166

South Asian (SAS) AF: 0.00418 AC: 20 AN: 4786

European-Finnish (FIN) AF: 0.000757 AC: 8 AN: 10574

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0110 AC: 746 AN: 67720

Other (OTH) AF: 0.00857 AC: 18 AN: 2100

Alfa AF: 0.00527 Hom.: 0

Bravo AF: 0.00709

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	PDZD7-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs397516634; hg19: chr10-102770309; COSMIC: COSV64651231; COSMIC: COSV64651231;