4-88065807-C-G

Variant names:

• chr4-88065807-C-G
• rs555242193
• NM_000297.4:c.2286C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000297.4(PKD2):​c.2286C>G​(p.Tyr762*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Y762Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD2 NM_000297.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.621
• Publications: 2 publications found

Genes affected

PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]

PKD2 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 2

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-88065807-C-G is Pathogenic according to our data. Variant chr4-88065807-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 997311.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.2286C>G	p.Tyr762*	stop_gained	Exon 12 of 15	NP_000288.1
	PKD2	NM_001440544.1		c.2061C>G	p.Tyr687*	stop_gained	Exon 11 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.2264C>G		non_coding_transcript_exon	Exon 11 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.2286C>G	p.Tyr762*	stop_gained	Exon 12 of 15	ENSP00000237596.2
	PKD2	ENST00000502363.1	TSL:5	c.540C>G	p.Tyr180*	stop_gained	Exon 5 of 8	ENSP00000425289.1
	PKD2	ENST00000508588.5	TSL:2	c.540C>G	p.Tyr180*	stop_gained	Exon 7 of 10	ENSP00000427131.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Polycystic kidney disease Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 p.Tyr762X variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, GeneInsight-COGR, LOVD 3.0, ADPKD Mutation Database, PKD1-LOVD, databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr762X variant leads to a premature stop codon at position 762 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. Please note another variant, c.2286C>A at the same position with different nucleotide change and same amino acid change, p.Tyr762X was found in ADPKD Mutation Database and was classified as Definitely Pathogenic. The c.2286C>A was also found in 2 families with ADPKD (Veldhuisen 1997). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		0.62
Vest4		0.95
GERP RS		-2.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs555242193; hg19: chr4-88986959;