NM_000297.4:c.17G>T

Variant names:

• chr4-88007750-G-T
• rs1307960365
• NM_000297.4:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000297.4(PKD2):​c.17G>T​(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,054,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26
• Publications: 4 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

ENSG00000286618 (HGNC:):

ENSG00000289034 (HGNC:58844):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2154252).

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.17G>T	p.Arg6Leu	missense	Exon 1 of 15	NP_000288.1	Q13563-1
	PKD2	NM_001440544.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.116G>T		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 15	ENSP00000237596.2	Q13563-1
	PKD2	ENST00000927447.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 15	ENSP00000597506.1
	PKD2	ENST00000927448.1		c.17G>T	p.Arg6Leu	missense	Exon 1 of 14	ENSP00000597507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000177 AC: 1 AN: 56642 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1054562 Hom.: 0 Cov.: 28 AF XY: 0.00000195 AC XY: 1 AN XY: 512698

African (AFR) AF: 0.00 AC: 0 AN: 20560

American (AMR) AF: 0.00 AC: 0 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14234

East Asian (EAS) AF: 0.00 AC: 0 AN: 14534

South Asian (SAS) AF: 0.0000246 AC: 1 AN: 40678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2872

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 891266

Other (OTH) AF: 0.00 AC: 0 AN: 38760

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Polycystic kidney disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.56	P
Vest4		0.20
MutPred		0.33		Loss of MoRF binding (P = 6e-04)
MVP		0.38
MPC		0.68
ClinPred		0.43	T
GERP RS		2.7
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.59
Mutation Taster		=75/25	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: rs1307960365; hg19: chr4-88928902;