chr4-88007749-C-A

Variant names:

• chr4-88007749-C-A
• NM_000297.4:c.16C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000297.4(PKD2):​c.16C>A​(p.Arg6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,053,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. R6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.658

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]

ENSG00000286618 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19469258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.16C>A	p.Arg6Ser	missense_variant	Exon 1 of 15	ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.16C>A	p.Arg6Ser	missense_variant	Exon 1 of 14		XP_011530330.1
PKD2	NR_156488.2	n.115C>A		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	c.16C>A	p.Arg6Ser	missense_variant	Exon 1 of 15	1	NM_000297.4	ENSP00000237596.2
ENSG00000286618	ENST00000662475.1	n.112+617G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1053240 Hom.: 0 Cov.: 28 AF XY: 0.00000195 AC XY: 1 AN XY: 512062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000225

Gnomad4 OTH exome AF: 0.0000259

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Polycystic kidney disease 2 Uncertain:1

Nov 29, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.048
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.39	B
Vest4		0.15
MutPred		0.36		Loss of MoRF binding (P = 3e-04);
MVP		0.27
MPC		0.64
ClinPred		0.57	D
GERP RS		2.7
Varity_R		0.49
gMVP		0.64

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: chr4-88928901;