4-88007770-G-C

Position:

• chr4-88007770-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The ENST00000237596.7(PKD2):​c.37G>C​(p.Gly13Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,031,908 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G13G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: PKD2 ENST00000237596.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21337363).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4	c.37G>C	p.Gly13Arg	missense_variant	1/15	ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.37G>C	p.Gly13Arg	missense_variant	1/14		XP_011530330.1
PKD2	NR_156488.2	n.136G>C		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.37G>C	p.Gly13Arg	missense_variant	1/15	1	NM_000297.4	ENSP00000237596	P1
	ENST00000662475.1	n.112+596C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.000132 AC: 6 AN: 45600 Hom.: 0 AF XY: 0.0000724 AC XY: 2 AN XY: 27632

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000204 AC: 21 AN: 1031908 Hom.: 0 Cov.: 28 AF XY: 0.0000221 AC XY: 11 AN XY: 498636

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: 0.0000239

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant polycystic kidney disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the PKD2 protein (p.Gly13Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PKD2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	Benign	0.11
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.88	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.044
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.046	B
Vest4		0.31
MutPred		0.33		Gain of solvent accessibility (P = 0.0012);
MVP		0.47
MPC		0.71
ClinPred		0.22	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs1228430587; hg19: chr4-88928922;