NM_001195263.2:c.2992_2993delCA

Variant names:

• chr10-101008575-CTG-C
• rs1471327428
• NM_001195263.2:c.2992_2993delCA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001195263.2(PDZD7):​c.2992_2993delCA​(p.Gln998AspfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000013 in 1,535,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PDZD7 NM_001195263.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.498
• Publications: 0 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)
• Usher syndrome type 2C

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0355 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.2992_2993delCA	p.Gln998AspfsTer5	frameshift	Exon 17 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.2989_2990delCA	p.Gln997AspfsTer5	frameshift	Exon 17 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.2992_2993delCA	p.Gln998AspfsTer5	frameshift	Exon 17 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.2989_2990delCA	p.Gln997AspfsTer5	frameshift	Exon 17 of 17	ENSP00000582249.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2939_*2940delCA		non_coding_transcript_exon	Exon 13 of 13	ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151652 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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 AF: 7.23e-7 AC: 1 AN: 1383900 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 682860

African (AFR) AF: 0.0000317 AC: 1 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078874

Other (OTH) AF: 0.00 AC: 0 AN: 57908

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151652 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000242 AC: 1 AN: 41266

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.50

Splicing

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

Other links and lift over

dbSNP: rs1471327428; hg19: chr10-102768332;