rs375164861

Variant names:

• chr4-88038464-G-A
• rs375164861
• NM_000297.4:c.1057G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PM2 PP3_Moderate PP5

The NM_000297.4(PKD2):​c.1057G>A​(p.Glu353Lys) variant causes a missense change involving the alteration of a 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV003195074: Identified in patients with renal cysts or a clinical diagnosis of polycystic kidney disease referred for genetic testing at GeneDx and in published literature (PMID:29038287)". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E353D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.89
• Publications: 0 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 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003195074: Identified in patients with renal cysts or a clinical diagnosis of polycystic kidney disease referred for genetic testing at GeneDx and in published literature (PMID: 29038287)
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000297.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• PP5: Variant 4-88038464-G-A is Pathogenic according to our data. Variant chr4-88038464-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477621.

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.1057G>A	p.Glu353Lys	missense	Exon 4 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.1057G>A	p.Glu353Lys	missense	Exon 4 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.1156G>A		non_coding_transcript_exon	Exon 4 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.1057G>A	p.Glu353Lys	missense	Exon 4 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.1057G>A	p.Glu353Lys	missense	Exon 4 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.1057G>A	p.Glu353Lys	missense	Exon 4 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.96
MVP		0.91
MPC		0.68
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.97
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs375164861; hg19: chr4-88959616;