4-88074903-C-T

Variant names:

• chr4-88074903-C-T
• rs755226061
• NM_000297.4:c.2614C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PP3_Moderate PP5_Very_Strong

The NM_000297.4(PKD2):​c.2614C>T​(p.Arg872*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000890204: Published functional studies demonstrate this variant results in the loss of PKD1 binding, reduction of IP3R binding and the loss of phosphorylation inhibiting cell growth (Qian et al., 1997" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R872R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PKD2 NM_000297.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19
• Conservation: PhyloP100: 1.55
• Publications: 22 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: ClinGen, Orphanet
• polycystic kidney disease 2

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

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000890204: Published functional studies demonstrate this variant results in the loss of PKD1 binding, reduction of IP3R binding and the loss of phosphorylation inhibiting cell growth (Qian et al., 1997; Li et al., 2005; Liang et al., 2008);; SCV003934434: At least one publication reports experimental evidence evaluating an impact on protein function, which suggests p.Arg872X PKD2 may be subject to endoplasmic reticulum-associated degradation (Liang_2008). PMID: 18178578, 16223735; SCV004174188: Functional studies showed an altered splicing behaviour of the altered mRNA and increased proteasomal degradation of the resulting protein (PMID: 10541293, 18178578). In addition, functional studies showed that the variant affects PKD1 binding as well as other functional deleterious consequences (PMID: 16223735, 18664456).; SCV001480740: Reverse transcription-PCR from patient lymphoblast RNA showed that the variant resulted in an out-of-frame splice variant by activating a cryptic splice site and the formation of three species of processed transcripts: a wildtype transcript, a transcript with a single base nonsense mutation, and an incorrectly spliced transcript with deletion which leads to a consequent frame shift resulting in a stop codon eight residues downstream of the splice junction; there was no exon skipping found (Reynolds 1999).; SCV005153473: RNA studies have demonstrated that this alteration results in abnormal splicing (Reynolds, 1999). Additionally, T lymphocytes from patients with this alteration showed a reduction of ATP-evoked calcium (Magistroni, 2019).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-88074903-C-T is Pathogenic according to our data. Variant chr4-88074903-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 448036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.2614C>T	p.Arg872*	stop_gained	Exon 14 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.2389C>T	p.Arg797*	stop_gained	Exon 13 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.2592C>T		non_coding_transcript_exon	Exon 13 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.2614C>T	p.Arg872*	stop_gained	Exon 14 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.2611C>T	p.Arg871*	stop_gained	Exon 14 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.2515C>T	p.Arg839*	stop_gained	Exon 13 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251096 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111962

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

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

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ 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

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
8	-	-	Polycystic kidney disease 2 (8)
1	-	-	Autosomal dominant polycystic kidney disease (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.6
Vest4		0.98
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: -2

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

Other links and lift over

dbSNP: rs755226061; hg19: chr4-88996055;