4-88008089-G-C

Variant names:

• chr4-88008089-G-C
• rs748654180
• NM_000297.4:c.356G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000297.4(PKD2):​c.356G>C​(p.Arg119Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,366,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R119H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76
• 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: Orphanet, ClinGen
• polycystic kidney disease 2

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ENSG00000286618 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12635317).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.356G>C	p.Arg119Pro	missense	Exon 1 of 15	NP_000288.1
	PKD2	NM_001440544.1		c.356G>C	p.Arg119Pro	missense	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.455G>C		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.356G>C	p.Arg119Pro	missense	Exon 1 of 15	ENSP00000237596.2
	ENSG00000286618	ENST00000662475.1		n.112+277C>G		intron	N/A
	PKD2	ENST00000506727.1	TSL:4	n.-143G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1366306 Hom.: 0 Cov.: 35 AF XY: 0.00000593 AC XY: 4 AN XY: 674160

African (AFR) AF: 0.00 AC: 0 AN: 29768

American (AMR) AF: 0.00 AC: 0 AN: 33760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24674

East Asian (EAS) AF: 0.00 AC: 0 AN: 34076

South Asian (SAS) AF: 0.00 AC: 0 AN: 77248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 0.00000561 AC: 6 AN: 1070334

Other (OTH) AF: 0.00 AC: 0 AN: 57134

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant polycystic kidney disease Uncertain:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 119 of the PKD2 protein (p.Arg119Pro). 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. 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.063
Sift	Benign	0.34	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.27		Loss of MoRF binding (P = 0.001)
MVP		0.14
MPC		0.77
ClinPred		0.78	D
GERP RS		3.2
PromoterAI		-0.079	Neutral
Varity_R		0.29
gMVP		0.21
Mutation Taster		=68/32	polymorphism

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: rs748654180; hg19: chr4-88929241;