4-88046767-T-A

Position:

• chr4-88046767-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000297.4(PKD2):​c.1445T>A​(p.Phe482Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F482C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-88046767-T-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39321762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.1445T>A	p.Phe482Tyr	missense_variant	6/15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.1445T>A	p.Phe482Tyr	missense_variant	6/15	1	NM_000297.4	ENSP00000237596	P1
PKD2	ENST00000508588.5	c.-199+3310T>A		intron_variant		2		ENSP00000427131

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.028
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.54	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.17
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.039	D
Polyphen		0.092	B
Vest4		0.46
MutPred		0.31		Gain of helix (P = 0.0425);
MVP		0.59
MPC		0.31
ClinPred		0.74	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.29
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs75762896; hg19: chr4-88967919;