Genetic Variant NM_000297.4:c.203delC (chr4-88007930-AC-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_000297.4(PKD2):c.203delC(p.Pro68ArgfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PKD2
NM_000297.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.393

Variant links:

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 links:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 4-88007930-AC-A is Pathogenic according to our data. Variant chr4-88007930-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 3720581.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-88007930-AC-A is described in Lovd as [Pathogenic]. Variant chr4-88007930-AC-A is described in Lovd as [Pathogenic]. Variant chr4-88007930-AC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.203delC	p.Pro68ArgfsTer49	frameshift_variant	Exon 1 of 15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6
PKD2	XM_011532028.3 link	c.203delC	p.Pro68ArgfsTer49	frameshift_variant	Exon 1 of 14		XP_011530330.1
PKD2	NR_156488.2 link	n.302delC		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.203delC	p.Pro68ArgfsTer49	frameshift_variant	Exon 1 of 15	1	NM_000297.4	ENSP00000237596.2		Q13563-1
ENSG00000286618	ENST00000662475.1 link	n.112+435delG		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150276

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000116

AC:

AN:

1295770

Hom.:

Cov.:

AF XY:

0.0000126

AC XY:

AN XY:

636876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000376

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000442

Gnomad4 EAS exome

AF:

0.0000352

Gnomad4 SAS exome

AF:

0.0000282

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000875

Gnomad4 OTH exome

AF:

0.0000188

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

150276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73374

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal dominant polycystic kidney disease

Pathogenic:1

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Pro68Argfs*49) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 22383692). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over