chr4-88065441-T-C

Variant names:

• chr4-88065441-T-C
• rs569788968
• NM_000297.4:c.2186T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L729Q) has been classified 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
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

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.2186T>C	p.Leu729Pro	missense	Exon 11 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.1961T>C	p.Leu654Pro	missense	Exon 10 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.2164T>C		non_coding_transcript_exon	Exon 10 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.2186T>C	p.Leu729Pro	missense	Exon 11 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.2186T>C	p.Leu729Pro	missense	Exon 11 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.2087T>C	p.Leu696Pro	missense	Exon 10 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant polycystic kidney disease (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	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
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs569788968; hg19: chr4-88986593;