4-88065441-T-C

Variant names:

• chr4-88065441-T-C
• NM_000297.4:c.2186T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000297.4(PKD2):​c.2186T>C​(p.Leu729Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.73

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.2186T>C	p.Leu729Pro	missense_variant	Exon 11 of 15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.2186T>C	p.Leu729Pro	missense_variant	Exon 11 of 15	1	NM_000297.4	ENSP00000237596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant polycystic kidney disease Uncertain:1

Oct 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 729 of the PKD2 protein (p.Leu729Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PKD2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKD2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.58		Loss of stability (P = 0.0038);.;.;
MVP		0.38
MPC		0.82
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-88986593;