chr10-101030023-C-A

Variant names:

• chr10-101030023-C-A
• rs1426679303
• NM_001195263.2:c.197G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001195263.2(PDZD7):​c.197G>T​(p.Arg66Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R66C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PDZD7 NM_001195263.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.29
• Publications: 4 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 2 ACMG points.

• 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.197G>T	p.Arg66Leu	missense	Exon 2 of 17	NP_001182192.1	Q9H5P4-3
	PDZD7	NM_001437429.1		c.197G>T	p.Arg66Leu	missense	Exon 2 of 17	NP_001424358.1
	PDZD7	NM_001351044.2		c.197G>T	p.Arg66Leu	missense	Exon 2 of 10	NP_001337973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.197G>T	p.Arg66Leu	missense	Exon 2 of 17	ENSP00000480489.1	Q9H5P4-3
	PDZD7	ENST00000912190.1		c.197G>T	p.Arg66Leu	missense	Exon 2 of 17	ENSP00000582249.1
	PDZD7	ENST00000645349.1		c.197G>T	p.Arg66Leu	missense	Exon 2 of 10	ENSP00000495283.1	A0A2R8YFN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	Hearing loss, autosomal recessive 57 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.49		Loss of MoRF binding (P = 0.003)
MVP		0.73
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.60
gMVP		0.79
Mutation Taster		=7/93	disease causing

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

Other links and lift over

dbSNP: rs1426679303; hg19: chr10-102789780;